Chapter 57. Anesthesia for Liver Surgery and Transplantation

1. Patients with chronic liver dysfunction and cirrhosis have a hyperdynamic circulation with low peripheral vascular resistance and an increased cardiac index.

2. Coagulopathies, edema and ascites, renal dysfunction, portopulmonary hypertension, hepatopulmonary syndrome, and autonomic neuropathies are common in patients with liver disease.

3. The cause of hepatic encephalopathy is believed to be multifactorial. Hepatic encephalopathy resembles and must be differentiated from many other nonfocal neurologic conditions such as hypoglycemia, hyponatremia, intracranial hemorrhage or mass lesions, and meningitis.

4. Patients scheduled for a hepatic resection should be evaluated as any patient scheduled for major noncardiac surgery. Plans for monitoring, vascular access, induction and maintenance of anesthesia, postoperative pain control, and postoperative care should take into account a large subcostal incision and the potential for sudden massive hemorrhage and severe physiologic derangements during and after surgery.

5. The most common indication for liver transplantation is chronic hepatocellular disease due to alcohol and/or hepatitis. Hepatitis C is increasingly important, representing a unique and growing health risk for anesthesiologists.

6. Cardiac assessment of the patient being considered for liver transplantation focuses on functional and invasive tests of cardiac performance that assess ischemic potential and the search for cardiac structural anomalies that might compromise outcome from orthotopic liver transplantation.

7. Liver transplantation comprises 3 phases. During the preanhepatic phase, a complete hepatectomy is performed. During the anhepatic phase, vascular anastomoses between the donor liver and the recipient's vessels are constructed. During the neohepatic phase, the hepatic arterial and biliary anastomoses are constructed, and the wound is closed.

8. The 2 common techniques for liver transplantation are the en-bloc technique with interruption of vena caval flow and the piggyback technique with preservation of vena caval flow.

9. The goals of hemodynamic management are to provide sufficient circulating volume, vascular tone, and cardiac output to perfuse the vital organs. This is not guided by any single parameter but rather by a synthesis of all available data.

10. The effects of portal hypertension and ascites are alleviated by nonshunting and shunting procedures. Nonshunting procedures are aimed at controlling hemorrhage from portosystemic varices. Shunting procedures redirect the portal venous flow into the systemic venous circulation via a nonvariceal conduit, thus relieving portal hypertension, decompressing varices, and at the same time relieving ascites.

11. Most livers made available for transplantation come from heart-beating cadaveric donors. When caring for organ donors, the focus of care has shifted from preserving the patient to preserving the function of graft organs. Due to the shortage of cadaveric donors, the use of living donors is growing. In these cases, donor safety is a primary concern, as the donor derives no physical benefit from the surgery.

Anesthesia for surgery of the hepatobiliary system is a challenging and rapidly evolving subspecialty of anesthesiology. The growth of this subspecialty has paralleled the evolution of hepatic surgery from a risky and heroic enterprise to a more routine undertaking over the past decades. Better understanding of hepatic anatomy, improved diagnostic imaging capabilities, enhanced patient selection and risk stratification, and technical advancements in surgical and anesthetic techniques have at once improved the morbidity and mortality profiles of liver surgery while extending the limits of what can safely be accomplished.

This chapter describes the anesthetic management of patients undergoing hepatic surgery, ranging from minimally invasive procedures, such as transjugular intrahepatic portosystemic shunting, to orthotopic liver transplantation (OLT). Patients presenting for hepatic surgery may generally be divided into 2 groups, each of whom provide unique challenges for the anesthesiologist:

1. Patients presenting for surgery on the liver who do not have significant liver disease—for example, the patient with isolated hepatocellular carcinoma. These patients can generally be evaluated and managed as patients presenting for other types of major intra-abdominal surgery.

2. Patients with significant liver disease presenting for hepatic surgery either to ameliorate the liver disease itself or, more rarely, for treatment of a distinct hepatobiliary problem. Hepatobiliary operations performed on patients with liver disease include portosystemic shunts, hepatic resection, and orthotopic liver transplantation.

Patients with liver disease who need nonhepatic surgery are a broader group unified by a common derangement. In these individuals, the liver disease must be taken into account and will shape the preoperative preparation, anesthetic technique, and postoperative care. For more details on the evaluation and general anesthetic management of the patient with liver disease presenting for nonhepatic surgery, the reader is referred to Chapter 15.

The general principles evinced in Chapter 15 apply as well to patients with liver disease presenting for hepatobiliary surgery. In this chapter, we first review the relevant anatomy, physiology, and hepatobiliary pathophysiology that affect the anesthetic management of patients presenting for hepatic surgery. Next, we describe at a high level the surgical considerations informing the various groups of hepatic operations, followed by detailed consideration of the consequent anesthetic management goals.

Anatomy of the Liver

The liver contains lobes (right and left) that are separated on the anterior side by the falciform ligament and supplied by right and left branches of the portal vein and the hepatic artery. Two smaller additional lobes may be visualized on the posterior aspect of the liver, the caudate and quadrate lobes. The liver is further subdivided into 8 segments that are defined by secondary and tertiary branching of the blood supply. The caudate lobe contains segment 1, the left lobe contains segments 2 and 3, the quadrate contains segment 4, and the right lobe contains segments 5 through 8.

Blood flow to the liver is 1 L/min-1/kg-1 of hepatic tissue, or approximately 25% of the cardiac output. Most of this blood supply is via the portal vein (75%), which delivers about 45% to 50% of the hepatic oxygen supply, with the balance coming via the hepatic artery. Portal venous blood flow is controlled primarily by the arterioles within upstream splanchnic organs and to a more limited extent by resistance within the liver. Hepatic artery blood flow is controlled directly via arterial smooth muscle under autonomic regulation. In addition, metabolic factors such as blood pH and/or oxygen content can also modulate hepatic arterial resistance and hence blood flow. After coursing through the liver, blood drains via the hepatic veins and into the inferior vena cava.

Overview of Liver Functions

The liver is among the most complex organs in the body and is responsible for a wide range of important synthetic and metabolic processes. A detailed review is beyond the scope of this chapter, but a brief overview is provided in the following.

Albumin Synthesis

The liver synthesizes more albumin than any other protein, in the range of 10 to 20 g/d. As the most abundant plasma protein, it serves an important role in maintaining the normal oncotic pressure of plasma, and a decrease in albumin synthesis can allow transudation of fluids into extravascular spaces, producing edema and ascites. Albumin has a half-life of approximately 20 days and therefore is not a good indicator of liver function in patients with acute hepatic disease. Because many drugs, including barbiturates and benzodiazepines, are bound by albumin in the blood, the hypoalbuminemia frequently observed in patients with significant hepatic dysfunction can lead to an increase in their free or active concentrations. This may, in part, account for the increased sensitivity of patients with severe hepatic disease to sedatives and anesthetics.

Coagulation Factor Synthesis

The liver is the major site of synthesis of most procoagulant and inhibitory clotting factors, including fibrinogen; factors II, V, VII, IX, XII, and XIII; plasminogen; antithrombin; and proteins C and S. Consequently, the loss of hepatic parenchymal cells can lead to clotting factor deficiencies with resultant coagulopathy. Systemic fibrinolysis, which is found in 30% of patients with end-stage liver disease, may also contribute to clotting factor deficiencies.1,2 Although the pathogenesis of this fibrinolysis has not been clearly defined, studies suggest that it involves altered tissue plasminogen activator activity, impaired synthesis of the inhibitors of plasminogen and plasmin, α-2 antiplasmin, and histidine-rich glycoprotein.3-7 Additionally, patients with advanced liver disease exhibit an exaggerated fibrinolytic response to major surgery, such as liver transplantation, predisposing them to significant perioperative hemorrhage.2,8

Carbohydrate Metabolism

Regulation of blood glucose concentrations is largely controlled by the liver and is under hormonal control. In response to lowered concentrations of glucose in the portal vein, glycogen stored in the liver is broken down to glucose for use by other tissues (glycogenolysis). During periods of fasting when glycogen stores have been depleted, the liver can also generate glucose from noncarbohydrate sources such as lactate, amino acids, and glycerol (gluconeogenesis). Ingestion of carbohydrates replenishes glycogen stores and allows fatty acids to be synthesized by the liver.

Bile Acid Synthesis

Bile acids are important compounds required for the elimination of cholesterol and the absorption of vitamins and fats. The liver converts approximately 500 mg/d of cholesterol into bile acids in processes that involve 17 different enzymes and are regulated by many factors, including nutrients and hormones.9,10 Bile acids are stored in the gall bladder and released into the small intestine to emulsify lipids, cholesterol, and the fat-soluble vitamins A, D, E, and K. Most (90%-95%) of the secreted bile acids are reabsorbed by the liver and recycled.

Drug Metabolism

Although there are a number of enzymatic pathways involved in the metabolism of drugs by the liver, each can be placed into 1 of 2 reaction categories. Phase 1 reactions use the chemical processes of oxidation, reduction, and hydrolysis; occur in the hepatocyte smooth endoplasmic reticulum; and are mediated primarily by the cytochrome P-450 family of enzymes. Phase 2 reactions increase the water solubility of drugs by coupling (conjugating) drugs with polar moieties, thereby facilitating biliary excretion. Often, phase 2 reactions follow phase 1 reactions because the products of phase 1 reactions may not be sufficiently water soluble to be readily excreted.

In this section, we briefly review the disease entities leading to liver failure. For a more complete description, the reader is referred to Chapter 15. Also in Chapter 15, the reader will find a discussion of the Child-Turcotte-Pugh classification scheme for evaluating the surgical risk associated with progressive worsening of liver disease. Later in this section, we describe the pathogenesis and medical management of organ system derangements that are associated with acute and chronic liver disease.

Chronic Liver Disease

Chronic liver disease may result from a variety of conditions, including infection, biliary obstruction, toxicity, and inborn errors of metabolism (Box 57-1). These conditions can progress to cirrhosis, which is characterized by hepatic cell death, fibrosis, and the formation of regenerative nodules. This process is essentially irreversible and leads to important physiologic disturbances. Elevation of the blood pressure within the portal venous system (ie, portal hypertension) is common in patients with significant chronic liver disease and results from increased portal blood flow and/or intrahepatic resistance. It is associated with the formation of ascites, esophageal varices, hepatic encephalopathy, and splenomegaly. Ascites is a hallmark of decompensated liver cirrhosis, and its cause is multifactorial. These factors include alterations in portal blood flow dynamics, activation of the renin-angiotensin-aldosterone system, and reduction in plasma oncotic pressure. The primary treatments for ascites are sodium and water restriction, administration of diuretics, and abdominal paracentesis, which can lead to intravascular fluid depletion.

Esophageal variceal bleeding is a potentially lethal complication of cirrhosis. Treatment options depend on the severity of the bleeding and include the administration of beta-blockers, variceal banding, sclerotherapy, and portosystemic shunting. As compared to variceal banding, carvedilol, a noncardioselective vasodilating beta-blocker, is more effective at preventing first bleeds in patients with high-risk varices.11 However, an important potential complication of portosystemic shunting is that it may cause or worsen existing hepatic encephalopathy.12,13

Fulminant Hepatic Failure

Fulminant hepatic failure is generally defined as severe hepatic dysfunction that occurs either in the absence of preexisting liver disease or in the presence of well-compensated liver disease. Drug toxicity, most frequently by acetaminophen, is the most common cause of fulminant hepatic failure (Box 57-2), followed by viral hepatitis. However, not uncommonly (17%), no causative agent is identified.14 Acute hepatic encephalopathy is a prominent clinical feature of fulminant hepatic failure and is associated with progressive brain swelling and an increase in intracranial pressure (ICP) that can result in brain herniation and death. In patients with fulminant hepatic failure, brain herniation is the most commonly identifiable cause of death found at autopsy.15 Regular neurologic examinations can be used to exclude dangerous brain swelling in patients who are awake and responsive. However, neurologic examinations cannot detect dangerous increases in ICP in encephalopathic comatose patients or those undergoing general anesthesia. Therefore, some centers regularly institute ICP monitoring during major surgery. However, such monitoring is controversial because patients with fulminant hepatic failure are commonly coagulopathic, and the placement of ICP monitors is associated with a significant (10%-20%) risk of intracranial bleeding,16,17 although recent studies suggest this can be done safely with the preadministration of recombinant activated factor VII (rFVIIa).18

Treatment of fulminant hepatic failure is supportive, and many patients recover. However, some patients do not recover and thus require liver transplantation. Regardless of the final path to resolution, supportive care aims to reduce the impact of severe encephalopathy and brain swelling. Mild hypothermia appears to be protective in patients with encephalopathy during acute liver failure awaiting liver transplantation, but this has not been unequivocally demonstrated by randomized studies.19,20 Similarly, barbiturates may be used to lower brain oxygen consumption as an additional temporizing measure.

Bacterial infection develops in up to 80% of patients with fulminant hepatic failure.21,22 These infections most commonly involve the respiratory and urinary systems.22 Acute infection may prevent transplantation.

Hemodynamic Changes in Liver Disease

Patients with chronic liver dysfunction and cirrhosis commonly have a hyperdynamic circulation (Box 57-3) with a low peripheral vascular resistance and an increased cardiac index.23 It has been suggested that a low systemic vascular resistance results from an increase in circulating endogenous vasodilators, including nitric oxide, calcitonin gene-related peptide, and substance P, the metabolism of which is reduced by the presence of intrahepatic and extrahepatic arteriovenous shunts.24-26 Cardiac output is frequently elevated in cirrhotic patients, attributable to increased sympathetic nervous system activity, increased blood volume and preload, and reduced systemic vascular resistance, and mimics hemodynamics seen in patients with extrahepatic portal vein obstruction.27-29 However, even in the setting of increased cardiac output, patients with cirrhosis may have significant cardiac dysfunction. Typical features of "cirrhotic cardiomyopathy" include impaired cardiac contractility, conduction abnormalities, impaired excitation-contraction coupling, and decreased β-adrenergic receptor function.30,31 Endogenous cannabinoids have been implicated in the progression of liver disease and subsequent development of cirrhotic cardiomyopathy, and the finding of CB receptor upregulation in liver disease patients suggests a role for targeting CB1 and CB2 receptors in the potential treatment of this disease.31,32 Some patients with a hyperdynamic circulation develop significant left ventricular failure after liver transplantation. It has been suggested that this is due to increased peripheral vascular resistance after relief of vasodilation by transplantation. With inotropes, mechanical ventilation, and close monitoring, results from small series suggest that these patients will survive.33

Renal Function in Patients with Liver Disease

Renal dysfunction is common in patients with liver disease and has at least 3 major causes.34 First, prerenal azotemia resulting from the overaggressive use of diuretics used to control ascites can result in rising BUN and creatinine concentrations, indicating worsening renal function. This usually responds to reducing the diuretic dose and gentle hydration. The second common cause of renal dysfunction in patients with liver disease is acute tubular necrosis in the setting of another acute, precipitating factor. In patients with liver disease, a common scenario is the development of a low-tone, sepsis syndrome in the setting of an infection, such as spontaneous bacterial peritonitis, followed by renal failure. Renal failure commonly develops in the setting of infection in patients with liver disease. For example, it has been reported that 27% of patients with cirrhosis and sepsis progressed to renal failure.35 Of these patients, renal failure was reversible in 76%,35 demonstrating that renal function tends to recover with the removal of the inciting insult. However, the mortality for patients with high Model for End-Stage Renal Disease (MELD) scores (ie, severe liver disease) was high.35 The third most common cause of renal failure in the cirrhotic patient is hepatorenal syndrome.36 The diagnostic criteria for hepatorenal syndrome are given in Box 57-4. Changes in serum sodium along with changes in creatinine and GFR indicate worsening renal function and decreased survival in this patient population.37

Hepatorenal syndrome is marked by a worsening of renal function as the liver disease progresses. Renal function will not recover unless there is an improvement in liver function.34 Temporizing measures to treat hepatorenal syndrome are based on theories of its pathophysiology. One such theory is that the inciting factor is the peripheral vasodilation that characterizes late cirrhosis.38 Serum levels of nitric oxide and L-arginine rise progressively in cirrhotic patients with worsening renal function.39 Decreased peripheral vascular resistance activates vasoconstrictor systems (eg, renin-angiotensin-aldosterone, antidiuretic hormone, and sympathetics), leading to renal vasoconstriction. This in turn leads to sodium and water retention and the formation of ascites. Another theory is that portal hypertension reduces blood flow to hepatocytes,40 which sense this as a manifestation of inadequate blood volume and activate a hepatorenal reflex to cause vasoconstriction and sodium and water retention. Thus the temporizing therapies for hepatorenal syndrome include both renal vasodilators and splanchnic vasoconstrictors. Splanchnic vasoconstrictors, such as vasopressin and its longer-lived relatives, are sometimes coadministered with a plasma expander such as albumin.34,41 For patients with liver transplantation as an option, this is the preferred treatment, and renal function typically recovers after transplantation.34,42 However, transplantation is complicated by the presence of renal failure, and renal replacement therapy for control of pH, serum potassium, and intravascular volume is frequently required for these patients. In patients who develop hepatorenal syndrome, cardiac dysfunction as indicated by low cardiac output precedes and may herald hepatorenal syndrome.43

The Pulmonary System in Liver Disease

Some patients with chronic liver disease and portal hypertension develop alterations in pulmonary physiology leading to 2 clinically distinct syndromes: portopulmonary hypertension and hepatopulmonary syndrome. Although these 2 syndromes can coexist in the same patient, management depends on appreciating the difference between portopulmonary hypertension and hepatopulmonary syndrome, and the therapeutic approaches to each.44,45

Portopulmonary Hypertension

Portopulmonary hypertension occurs most frequently in patients with advanced liver disease. In 1 study of patients with cirrhosis and refractory ascites, the prevalence of portopulmonary hypertension was 16%.46 Portopulmonary hypertension is characterized by a mean pulmonary artery pressure greater than 25 mm Hg with a normal pulmonary capillary wedge pressure (ie, <15 mm Hg) and an elevated pulmonary vascular resistance (ie, >120 dyne/s/cm5) in the setting of portal hypertension.45 Multiple factors have been implicated in the etiology of portopulmonary hypertension, including (1) increased pulmonary arterial blood flow secondary to the increase in cardiac index frequently observed in cirrhosis, (2) increased circulating blood volume, and (3) vasoconstriction and progressive pulmonary vascular remodeling due to a proliferation of endothelial and smooth muscle cells with or without thrombotic change.45,47 The most common symptom of portopulmonary hypertension is dyspnea on exertion, with fatigue, palpitations, chest pain, and syncope being less frequent.48,49

Evidence of portopulmonary hypertension may be obtained noninvasively using transthoracic Doppler echocardiography. Figure 57-1 outlines the diagnostic approach to pulmonary hypertension. Although transthoracic echocardiography is a useful screening tool for portopulmonary hypertension, it frequently overestimates right ventricular pressure,50 producing a large number of false positives as determined by direct pressure measurements at subsequent cardiac catheterization.50,51 For example, a right ventricular systolic pressure estimate from transthoracic echocardiography of 40 mm Hg or greater is associated with significant pulmonary hypertension (ie, mean pulmonary artery pressure >25 mm Hg) at right heart catheterization in only about 65% of cases.51 Conversely, the sensitivity of Doppler echocardiography for detecting portopulmonary hypertension is high enough that a normal study rules out portopulmonary hypertension.51 Because of the severe consequences of failing to diagnose and manage portopulmonary hypertension during later liver surgery or transplantation, the best current approach is to screen with transthoracic echocardiography and perform pulmonary artery catheterization to confirm or exclude portopulmonary hypertension in patients with high right ventricular systolic pressure estimates at transthoracic echocardiography. Although moderate to severe portopulmonary hypertension is often a contraindication to hepatic transplantation, there are case reports of such patients undergoing successful hepatic transplantation with resolution of the pulmonary component of their disease.52

The effective management of portopulmonary hypertension is important because reducing pulmonary artery pressures, unloading the right heart, and allowing time for pulmonary vascular remodeling may allow patients who are not liver transplant candidates to become potential recipients.53 Pulmonary vasodilator treatment may also allow a marginal patient to receive a transplant with reduced mortality.53 Vasodilators, such as epoprostenol, sildenafil, or nitric oxide, can reduce pulmonary vascular resistance54,55 and are used for this purpose by programs that consider liver transplantation in patients whose pulmonary pressures can be satisfactorily lowered. However, it is unclear with the current level of evidence whether these interventions improve survival at liver transplantation. It is also unclear how long pulmonary artery pressures must be lowered to confer the benefit (if any) of the intervention at subsequent transplantation. Case reports of patients with good response to pulmonary vasodilators who subsequently have poor outcomes of transplantation temper enthusiasm about the prospects for such patients.56

Experience with pulmonary vasodilators is greatest with intravenous epoprostenol. Epoprostenol appears to be effective in reducing pulmonary artery pressures, although it can lead to splenomegaly.57 Epoprostenol use was a more common feature of patients with pulmonary hypertension who survived liver transplantation than it was in nonsurvivors with the same degree of pulmonary hypertension, although the difference was not significant.58 Unfortunately, intravenous epoprostenol requires continuous intravenous access for infusion, with all of the attendant complications of permanent venous access and pump failures.

The difficult logistics of continuous epoprostenol use have prompted a search for more convenient routes of administration and/or longer-lived prostaglandin analogues. For example, early reports indicate that continuous subcutaneous administration of treprostinil59 reduces the symptoms of pulmonary hypertension and lowers pulmonary artery pressures. Oral beraprost60 also reduces symptoms of pulmonary hypertension, but the reductions in pulmonary artery pressures were modest and did not achieve statistical significance despite a relatively large sample size. Inhaled iloprost reduces right heart pressures quickly and is easy to deploy (and should be pulmonary selective).61-63 In a recent study looking at both acute and long-term effects of iloprost on hepatic and pulmonary function in patients with portopulmonary hypertension, pulmonary vasodilation was immediately improved in treated patients without altering hepatic hemodynamics. At 12 months of follow-up, patients were clinically improved with an increased exercise capacity.64 It should be noted that none of the above-mentioned alternatives to intravenous epoprostenol produce more than a few millimeters of mercury reduction in the mean pulmonary artery pressure. Consequently, these drugs may have limited effectiveness in preparing patients with pulmonary hypertension for liver transplantation. Conversely, results from individual patients indicate that intravenous epoprostenol can lower the mean pulmonary artery pressure from approximately 50 to 25 mm Hg.54,65

The discovery that nitric oxide can induce pulmonary vasodilation has provided another approach to lowering pulmonary arterial pressures. Inhaled nitric oxide is a selective pulmonary vasodilator that lowers pulmonary artery pressures in patients with portopulmonary hypertension.55 Nitric oxide administered by face mask can be used as a diagnostic tool to assess pulmonary artery pressure response to vasodilators during right heart catheterization.66

When pulmonary hypertension is discovered unexpectedly in the operating room (OR) at the beginning of a transplant, reversible causes of pulmonary hypertension, such as hypoventilation-induced hypercarbia, should be ruled out or reversed. Figure 57-2 illustrates apparently severe pulmonary hypertension, with pulmonary pressures equal to the systemic pressure. Reversal of hypercarbia attributable to hypoventilation and lightening the anesthetic lowered the pulmonary pressures and raised the systemic pressures, after which the patient had an uneventful liver transplant.

When newly discovered apparent pulmonary hypertension does not respond to such simple maneuvers, inhaled nitric oxide may be very effective in lowering the pulmonary artery pressures acutely, without the systemic effects of a nonselective vasodilator such as epoprostenol. It is probably important to lower the pulmonary artery pressures (and consequently the central venous pressure) as effectively as possible, both to minimize hemorrhage and to avoid acute graft congestion that could cause early graft compromise in the OR.45 It is also important to extend the treatment of pulmonary hypertension well into the postoperative period, as graft failure due to poor blood flow remains a concern. Thus as the patient moves toward extubation, it is necessary to transition from inhaled nitric oxide to an intravenous agent (eg, epoprostenol) or an oral agent (eg, sildenafil) as part of weaning from the ventilator, with the lowest achievable pulmonary artery pressure being the goal.

Sildenafil is an inhibitor of phosphodiesterase 5 (PDE5), which blocks degradation of cyclic guanosine monophosphate, the second messenger of nitric oxide. Sildenafil also produces selective pulmonary vasodilation.67 There are early anecdotal reports of its use as a pulmonary vasodilator in pre–liver transplant patients.68,69 Oral sildenafil is also a useful adjunct to inhaled iloprost, a prostacyclin analogue.70 To date, there is far less evidence to support the efficacy of sildenafil, particularly as monotherapy, than there is for intravenous epoprostenol as therapy for portopulmonary hypertension, but early reports are encouraging.

In addition to PDE inhibitors, endothelin receptor antagonists have proven effective in treating pulmonary hypertension in patients with portopulmonary hypertension. Bosentan, an endothelin receptor antagonist, has been used successfully in lowering pulmonary artery (PA) pressures in this patient population.71 Compared to iloprost, patients treated with bosentan had higher survival rates at 1, 2, and 3 years.72 However, the use of bosentan in the treatment of pulmonary hypertension may not be effective in patients with concomitant heart failure.73

Hepatopulmonary Syndrome

Hepatopulmonary syndrome is defined by the presence of hepatic dysfunction or portal hypertension, an elevated alveolar-arterial oxygen gradient, and intrapulmonary vasodilation.74 Thus, although portopulmonary hypertension is associated with pulmonary vascular vasoconstriction, hepatopulmonary syndrome results from vasodilation and pulmonary vascular remodeling. Patients may present with digital clubbing, spider angiomata, arterial hypoxemia, and dyspnea that worsens upon moving from a recumbent to an upright position (orthodeoxia and platypnea).74 Early diagnostic criteria required ruling out the presence of other cardiopulmonary abnormalities. However, it is now apparent that hepatopulmonary syndrome may contribute to hypoxemia even when other cardiopulmonary abnormalities are present.75,76 Intrapulmonary vasodilation may reflect true anatomical shunt, physiologic shunt, and precapillary or capillary dilation, leading to alterations in oxygen diffusion.77 Nitric oxide is elevated in the exhaled breath of patients with hepatopulmonary syndrome, suggesting a causative role.78,79 Interestingly, there is a case report of normalization of exhaled nitric oxide accompanied by return to normoxia after liver transplantation.79

The diagnosis of hepatopulmonary syndrome depends on documenting the presence of arterial desaturation and pulmonary vasodilation in patients with liver disease. Other causes of hypoxia in patients with liver disease (Box 57-5) must be excluded. Pulse oximetry is a sensitive, noninvasive screening tool for detecting low arterial oxygen saturation, the results of which can be confirmed using arterial blood gas analysis and echocardiography.80 Pulmonary vasodilation can be documented using a variety of modalities, including contrast echocardiography, lung perfusion scanning, or pulmonary artery catheterization.45,81 During contrast echocardiography, late appearance (ie, 3-6 cardiac cycles) of contrast in the left heart suggests intrapulmonary shunting, whereas early appearance (immediate to 1 cardiac cycle) indicates intracardiac shunting.45 Pulmonary angiography is rarely indicated but may be useful to exclude or embolize arteriovenous malformations causing large right-to-left shunts.45 A flow chart outlining the assessment for hepatopulmonary syndrome is shown in Fig. 57-3.

There are no effective medical therapies for hepatopulmonary syndrome, although selective inhibition of nitric oxide production shows theoretical promise.45,81 For patients with end-stage liver disease, liver transplantation frequently leads to reduced intrapulmonary shunting and improved oxygenation.82 Transplantation in patients with hepatopulmonary syndrome is no riskier than transplantation in patients without hepatopulmonary syndrome, as the outcomes of transplantation are the same whether the recipients have the condition or not.83,84 Among patients with hepatopulmonary syndrome, orthotopic liver transplantation leads to longer survival than medical management without transplantation.85 Furthermore, cirrhotic patients with hepatopulmonary syndrome are more likely to die with medical therapy alone (as opposed to transplantation) than matched cirrhotic control patients without hepatopulmonary syndrome.85,86 However, it is important to transplant hepatopulmonary syndrome patients early; delaying transplant until patients are profoundly hypoxemic is associated with mortality as high as 30%.87,88

The Nervous System in Liver Disease

Hepatic Encephalopathy

It is generally believed that the cause of hepatic encephalopathy (HE) is multifactorial. Elevated ammonia levels are frequently but not always found in patients with HE, and it is traditionally believed that ammonemia plays a role in its development. Patients with higher gut-ammonia levels have an increased incidence of HE, and those patients with delayed gastric emptying secondary to diabetes mellitus have more severe HE as compared to nondiabetic cirrhotic patients.89 Activation of γ-aminobutyric acid (GABA) receptors in the brain may also contribute to HE, as evidenced by the ability of the GABAA-receptor-antagonist flumazenil to produce a short-term improvement in HE.90,91 Interestingly, ammonia has been shown to enhance GABAergic currents, perhaps explaining its role in HE.92 In animal models examining GABA modulation in hepatic encephalopathy, chronic hyperammonemia in rats is associated with increased GABAergic tone in the cerebellum with resultant cognitive impairment, and GABAergic tone in the cortex is decreased.93 Hepatic encephalopathy resembles many other nonfocal neurologic conditions (Box 57-6) from which it must be differentiated. Many of these occur as comorbid conditions in patients with liver failure. The severity of encephalopathy contributes to the Child-Turcotte-Pugh system for stratifying the severity of hepatic disease, as described in Chapter 15.

Autonomic Neuropathy

Autonomic neuropathies are found in up to 50% of patients with chronic liver disease.94,95 This is most commonly manifested as impaired cardiovascular function95 and gastric motility.96 In addition, patients with autonomic neuropathies experience a higher incidence of hypotension during general anesthesia.97 More importantly, autonomic neuropathy predicts increased mortality in cirrhotic patients relative to cirrhotic controls without autonomic neuropathy.98 The development of autonomic neuropathies is not dependent on the etiology of the liver disease, and studies have not consistently found a correlation between the severity of liver disease and the incidence of autonomic neuropathies. Importantly, autonomic neuropathies resolve with the return of normal liver function after transplantation.95,99

Indications and Patient Characteristics

Hepatic resection is performed to remove lesions in the liver by resecting either an entire hepatic lobe, 1 or more anatomic segments of the liver, or nonanatomic wedges of liver tissue. Such operations were first reported in the 1950s and for the next 30 years were considered to be high risk. For example, the rate of mortality from hepatic resection reported in 1977 was 13% to 20%, depending on the extent of the resection.100 Many of these deaths were due to hemorrhage. However, during the 1990s improved surgical and anesthesia techniques, along with a growing operative experience and an increased ability to plan resections, have reduced perioperative mortality. The current perioperative mortality for hepatic resections performed in high-volume centers is estimated to be 1% to 7%.101-105 In addition, multiple trends in morbidity and mortality are developing. In 1 center, the number of hepatic segments resected declined during the 1990s, and a concomitant decline in mortality has been demonstrated.101 At the same time, high-volume centers performing hepatic resections are liberalizing their acceptance criteria for patients, operating on older patients with more comorbid illnesses, including liver dysfunction, all while sustaining reductions in morbidity and mortality.105 Advanced age (ie, >70 years) is no longer a contraindication to hepatic resection for primary hepatocellular carcinoma or for metastases from other cancers.106-108 Furthermore, even patients with significant cirrhosis and liver dysfunction tolerate hepatic resections, in part because operative approaches now allow shorter hepatic ischemic time and the removal of less liver tissue, all while achieving satisfactory surgical margins.109 Even in patients with cirrhosis, morbidity from hepatic resections ranges from 20% to 50% (comparable with that reported in noncirrhotic cohorts), and mortality ranges from 0% to 10%.109

Long-term outcomes after hepatic resection are also reasonable: after resection of hepatocellular carcinoma, the 3-year survival ranges from 40% to 70%, whereas 5-year survival ranges from 40% to 50%.109 Even hepatic resections for metastatic cancer (eg, colon) have 1-, 3-, and 5-year survival rates of 90%, 54%, and 34%, respectively.110

Most patients present for hepatic resection due to malignancy (Box 57-7). In the United States, approximately 90% of patients in 1 large series had a malignancy; 69% of these were metastatic lesions, and 80% of these were colorectal in origin, making metastatic colon cancer the leading cause for hepatic resection.101 In Asia, the ratio of malignant to benign indications for hepatic resection is similar, but three-fourths of the malignancies are hepatocellular carcinoma,105 reflecting the regional heterogeneity of the distribution of this cancer. Together, these 2 studies report on more than 3000 patients undergoing hepatic resection between roughly 1990 and 2000.101,105 With such large numbers it was possible for the authors to conduct multivariate analyses to detect factors associated with increased risk of morbidity and mortality in the perioperative period after hepatic resection. Multivariate analysis yielded the following factors associated with elevated morbidity: blood loss, number of hepatic segments resected, added major biliary procedure, low preoperative albumin, presence of 1 or more comorbid conditions, male gender, elevated serum creatinine, added major vascular procedure, and thrombocytopenia.101,105 Risk factors for elevated mortality include blood loss, number of segments resected, preoperative bilirubin, complex hepatic resection, preoperative platelet count, low preoperative albumin, and patient age.101,105

Currently, most hepatic resections are performed for cancer. However, the major modes of therapy are in flux. State-of-the-art therapy for hepatocellular carcinoma includes radiofrequency ablation, hepatic resection, or orthotopic liver transplantation, depending on the number, size, and location of the lesions. Thus minimally invasive destructive therapies may significantly reduce the need for major hepatectomy in future.109

Operative Considerations for Hepatic Resection

After the incision for hepatic resection, the abdomen is explored for metastases. If previously unsuspected widely metastatic disease is found, the operation ends quickly. Therefore, large doses of long-acting opioids and paralyzing agents should be avoided in the initial stage of surgery. If a large volume of ascites is drained immediately after the incision, hemodynamic instability may ensue due to sudden shifts of fluid out of the intravascular system with a resultant drop in central venous pressure (CVP). Often, treatment with crystalloid or colloid replacement may be warranted to correct profound hypotension.

After the initial exploration, a self-retaining retractor (Bookwalter or equivalent) is placed to ensure good exposure. The placement of the retractor itself can depress splanchnic venous return and compromise respiratory mechanics by compressing the lung and overlying ribs.

The liver is dissected free of its attachments as needed to gain exposure, first to establish control of the vasculature and then to complete the hepatic resection. This involves moving the liver to gain exposure to the vascular structures underneath, which may twist the liver on its vascular pedicle or compress the vena cava, both leading to sudden changes in venous return with consequent hemodynamic effects. Careful observation of the surgical field and good communication between surgeon and anesthesiologist are essential. After gaining vascular control, the surgeon usually attempts to create anatomic planes (ie, ones that will bleed relatively little) between liver segments, or a dissection for a formal hepatic lobectomy is performed. Again, discussion with the surgeon prior to incision as to whether an anatomic or nonanatomic resection is planned is an essential component of the anesthetic plan.

It is important to understand the techniques for hepatic vascular occlusion during hepatic resection, as uncontrolled and massive blood loss is still a major risk of the operation. There are multiple hepatic vascular occlusion techniques, each with implications for the anesthesiologist.111 These are illustrated in Figs. 57-4, 57-5, and 57-6. In one common vascular exclusion maneuver, a clamp is placed on the portal triad. In this case, "portal triad" encompasses the hepatic artery, portal vein, and the common bile duct (Fig. 57-4).

Total vascular exclusion techniques allow "bloodless" surgery. In addition to clamping the portal triad, clamps are placed on the inferior vena cava above and below the liver (Fig. 57-5). This combination of clamps prevents both inflow of blood and backflow from the vena cava. In one report using total vascular exclusion, the average red cell transfusion was 2.2 units.112 Selective techniques have been described for total vascular exclusion in which the hepatic veins are clamped rather than the inferior vena cava.113 Portal triad clamping is accompanied by venous outflow clamping of either all of the hepatic veins or only those draining the resected territory (Fig. 57-6). In the report mentioned previously, most patients received no transfusion.113 Vascular exclusion techniques were first described by Pringle and are collectively described as the "Pringle maneuver." During vascular exclusion, the liver is warm and ischemic, so great attention is paid to keeping track of and minimizing "Pringle time." In a study comparing the Pringle maneuver with hemihepatic vascular inflow occlusion and main portal vein occlusion techniques, the Pringle maneuver was performed in a significantly shorter period of time, but postoperative liver recovery was better in both the hemihepatic and main portal occlusion techniques.114

At the conclusion of the resection, hemostasis is obtained and the incision is closed. These portions of the procedure can be lengthy and deserve attention, as control of hemorrhage is the key to a successful early postoperative period. During the latter phases of the operation, the anesthesia team should make plans for postoperative disposition, either to the recovery room or to an intensive care unit (ICU) if the insult from surgery has been severe.

Anesthesia for Hepatic Resection

Anesthesia for hepatic resection is appropriately changing over time and corresponds to the improvements in surgical technique and changes in patient selection.115,116 In general, patients scheduled for a hepatic resection should be evaluated as any patient scheduled for major noncardiac surgery. Plans for monitoring, vascular access, induction and maintenance of anesthesia, postoperative pain control, and postoperative care should take into account a large subcostal incision and the potential for sudden massive hemorrhage and severe physiologic derangements during and after surgery.

The history and physical examination includes a typical preanesthetic history, including questions directed to assess hepatic synthetic function, as well as global and focal neurologic status. For example, evidence of hepatic encephalopathy should be sought, both from the patient and any escorts present. Significant encephalopathy predicts worsened postoperative neurologic status if a hepatic resection or portal diversion is planned. Focal neurologic deficits (ie, sensory, motor, or pain abnormalities localized to a body part) should be sought and documented, as the procedures require prolonged immobility and positioning injuries may occur.

The assessment of cardiac ischemia risk cannot be overemphasized, as hepatic resections are frequently characterized by significant hemorrhage, leading to hypotension and tachycardia that may persist for some time as the anesthesia team restores intravascular volume. In addition to derangements in myocardial oxygen supply and demand during the case, the surgical stress induces a proinflammatory state. Major liver resection also leads to a hyperdynamic state with increased cardiac output and decreased systemic vascular resistance in the postoperative period.117,118 Thus the patient should be questioned in detail about risk factors pertaining to coronary artery disease as well as his or her level of physical activity and exercise tolerance. Symptoms of angina or anginal equivalents should be carefully sought.

The laboratory examination prior to hepatic resection includes an assessment of hepatic synthetic function (albumin, clotting factors as assessed by prothrombin time [PT], partial thromboplastin time [PTT], and fibrinogen measurement), metabolic function (aspartate aminotransferase [AST], alanine aminotransferase [ALT]), and excretory function (bilirubin). Assessment of coagulation function (PT, PTT, platelet count), oxygen-carrying capacity (hematocrit), and serum electrolytes completes the general picture of the patient. It is useful to obtain a chest x-ray to assess lung volumes and the status of the lung parenchyma and to search for preoperative pleural effusions (common in patients with significant liver disease, but rare in others).

Preoperatively, it may be useful to obtain a transthoracic echocardiogram to assess resting atrial and ventricular function and valve performance, and to exclude (within the power of this relatively noninvasive test) septal defects that might allow paradoxical embolization. As mentioned previously, cardiac risk stratification begins with careful history taking but should include functional testing indicated by the history and the guidelines of the American Heart Association.119

Preanesthetic Planning

Hepatic resections are almost always performed in supine position through a right-sided subcostal incision, although smaller resections may be approached initially via mini laparotomies in conjunction with laparoscopic instrumentation. There may be extensions either into the left subcostal region, superiorly in the midline, or both. The area of the surgical prep usually includes the entire abdomen and the lower chest up to the nipples. Monitor placement, warming strategies, and pain management planning should account for this.

Typical monitoring consists of standard monitors and selected invasive monitors directed toward managing problems likely to arise during the case. An arterial catheter is useful for early recognition of hypotension and for obtaining blood samples. Central venous pressure measurement is useful to guide intravascular volume replacement and to assess right heart pressures when a large hepatic resection is planned or when the dissection is expected to be bloody. If a low CVP technique is planned, CVP monitoring is essential. Central venous access has the added benefit of providing a conduit for potent vasopressor administration. A pulmonary artery catheter is useful for measuring pulmonary artery pressures, assessing left heart filling pressures, and guiding pharmacologic therapy. Transesophageal echocardiography can also provide information regarding both intravascular volume status and cardiac performance, and may replace invasive pressure measurements if the potential need for central venous access as a conduit for vasopressors is judged to be low.

Peripheral vascular access with sufficiently large catheters (eg, 14 gauge or larger) is usually sufficient for a hepatic resection. One helpful device is called the rapid infusion catheter (RIC, Arrow International, Reading, PA, USA). The RIC is a 6.4 cm × 7.0 or 8.5 French peripherally inserted catheter useful for rapid infusion of large volumes. It can be placed in any large peripheral vein. Antecubital or cephalic veins are commonly chosen, but even distal veins on the forearm and hand can be used if they are large enough. The RIC alleviates the need for multiple central lines that might be required to pass a pulmonary artery catheter, run multiple infusions, and accommodate the high-flow administration of large volumes.

Induction and Maintenance of Anesthesia

Induction of anesthesia is readily accomplished using standard methods. Major considerations for induction are directed toward comorbidities (gastroesophageal reflux disease, coronary artery disease, etc) rather than any unique feature of the liver disease. Patients with ascites should be considered to have a full stomach and receive a rapid-sequence induction with cricoid pressure, if not otherwise contraindicated.

Maintenance of anesthesia is also by standard methods, with attention to homeostatic control. Patient warming is important to maintain good clotting performance and to minimize the risk of surgical site infection.120,121 A single forced-air warming unit applied to the upper chest, arms, and head is usually sufficient, although underbody warming may be preferred. Intravenous fluids should either be warm or be actively warmed during infusion.

As large hepatic resections may produce transient hepatic dysfunction, it may be preferable to choose drugs whose elimination is not completely dependent on hepatic metabolism. In general, all usual techniques for the maintenance of general anesthesia are acceptable, although there are some minor differences between drugs commonly chosen for maintenance. Compared with isoflurane, sevoflurane was associated with smaller elevations in liver enzymes after hepatic segmentectomy.122 These were of uncertain clinical relevance, as no clinical liver damage was detected in either group. However, later comparison between sevoflurane and desflurane showed desflurane to be superior to sevoflurane in terms of postoperative hepatic and renal function at equipotent doses of 1 minimum alveolar concentration (MAC).123Cis-atracurium, atracurium, and remifentanyl might be more reliably eliminated than drugs that depend on hepatic hydrolysis and/or conjugation for termination of their effect. In practice, the dose-to-effect mode of administration is almost always sufficient to minimize the interaction between choice of anesthetic and the effect of liver resection.

If an epidural catheter has been inserted, it may be used intraoperatively with the understanding that the associated sympathetic blockade may cause hypotension. The severity of the hypotension correlates with the concentration and volume of local anesthetic administered. Conversely, relatively dilute local anesthetic (eg, 0.25% bupivacaine, 7-10 mL/h after a bolus) or dilute mixtures of local anesthetic combined with an opioid are likely to provide significant analgesia during general anesthesia, with little hemodynamic effect. If hypotension results from local anesthetic-induced sympathetic blockade, then it can be effectively treated with an infusion of a vasopressor such as phenylephrine or norepinephrine.

Goals for Oxygenation and Ventilation

Changes in FIO2 and ventilation predictably result in changes in liver oxygenation and CO2 elimination.124 Vascular exclusion techniques to reduce bleeding create periods of hepatic ischemia. Thus it seems prudent to provide normal systemic conditions by ventilating to keep the pH normal and the oxygen saturation high so that the liver is best prepared to tolerate these insults.

Hemodynamics

Clamping the portal triad reduces venous return, and one would expect cardiac output and blood pressure to fall. Cardiac output does indeed fall, but the blood pressure increases due to an increase in systemic vascular resistance evoked by portal triad clamping. This appears to be a neurally mediated reflex, as the increase in systemic vascular resistance can be ablated by infiltrating the portal triad with lidocaine prior to clamping.125 In contrast to portal triad clamping, total vascular exclusion of the liver via a vena cava cross clamp does reduce blood pressure concomitant with a fall in cardiac output because the loss of venous return is so much larger.

Bleeding and Coagulation

Blood loss is affected by central venous pressure during surgery. When central venous pressure is maintained below 5 cm H2O, blood loss is predictably lower than when central venous pressure is 6 cm H2O or greater. In the original publication describing low central venous pressure approaches to hepatic resection, the median blood loss was only 200 mL, with most patients in the low central venous pressure study group avoiding transfusion.126 In contrast, when the central venous pressure was 6 cm H2O or greater, the median blood loss was 1 L, and half of the patients required transfusion.126 Other centers practicing low central venous pressure techniques for hepatic resection report average estimated blood losses of about 1 L.104

Low central venous pressure approaches affect outcomes beyond transfusion and blood loss, as reflected in longer hospital stays for patients whose central venous pressure was greater than 6 cm H2O during hepatic resection.127 Blood loss (and the subsequent requirement for transfusion) is associated with longer hospitalization, greater perioperative morbidity, and a doubling of the perioperative mortality (from 1.2% to 2.5%).110 Authors in the surgical literature caution that extreme care must be taken during the dissection of the liver so as not to make holes in the hepatic veins, which can lead to catastrophic hemorrhage or air embolism.128 Obviously, the risk of severe air embolism is elevated under low central venous pressure conditions, and the anesthesia team must be highly vigilant for such an event.

Low central venous pressure anesthesia is apparently safe with respect to renal function, as only 3% of patients experience any degree of permanent renal dysfunction after hepatic resection using a low central venous pressure technique.104 This was lower than the historical incidence of renal failure complicating hepatic resection without the use of low central venous pressure.104 However, these favorable outcomes are predicated on maintaining good renal perfusion pressure (typically believed to be 60 mm Hg or more) and renal blood flow throughout surgery.116 In a recent study evaluating the effects of β-adrenergic agents on liver oxygenation during hepatectomy, patients receiving low-dose dopamine (4 mcg/kg/min) had improved hepatic oxygen supply and uptake as compared to controls during hepatectomy with low CVP technique.129

Control of Clotting

Multiple drugs that modify clotting are available to minimize blood loss during hepatic resection. Pharmacologic aids to minimize blood loss are attractive given the concerns regarding transfusion in cancer surgery, but they are no substitute for good surgical technique. A complete discussion of the use of procoagulants during liver surgery appears in the section Liver Transplantation. Briefly, 3 classes of agents are available: those that modify platelet and von Willebrand factor function (desmopressin and its analogues), the antifibrinolytics (aprotinin, ϵ-aminocaproic acid, and tranexamic acid), and direct replacement of specific clotting factors (eg, recombinant factor VII).

Desmopressin increases factor levels and improves laboratory measures of clotting during hepatectomy but has no effect on blood loss.130 The antifibrinolytic drug aprotinin reduces blood loss during elective liver resection,131 as demonstrated in a small prospective trial. However, a large multicenter outcome study comparing aprotinin with the other antifibrinolytics and placebo in cardiac surgery demonstrated that the drug is not superior to ϵ-aminocaproic acid or tranexamic acid for reducing blood loss.132 Aprotinin is, however, associated with excess renal failure and mortality compared with the other alternatives in cardiac surgery.132 Therefore, routine use of aprotinin during hepatic resection must be questioned until studies demonstrating its safety in large numbers of hepatectomy patients appear. Recombinant factor VII does not reduce blood loss or transfusion requirements in patients undergoing major hepatic resections,133 but off-label use of this drug has been associated with unwanted thrombotic complications.134

Postoperative Planning

Postoperative planning after hepatectomy addresses 3 major concerns: immediate postsurgical airway management, postoperative disposition, and pain management.

Assessment of the airway after surgery and planning for extubation are guided by the same considerations as applied to any major case with the potential for large volume shifts and with a high abdominal incision. First, the magnitude of the operation and the patient's preoperative functional status are inventoried, followed by the magnitude of hemorrhage and the adequacy of its replacement, manifested by hemodynamic stability and acid–base status. Factors within the anesthesiologist's control (ie, patient temperature, sedation, residual general anesthetics, and muscle strength) are considered. A physical examination of the face and upper airway assesses the degree of edema and swelling that might compromise the extubated airway. If all of these considerations are judged to be in satisfactory order, then it is reasonable to extubate the trachea at the end of a hepatic resection; otherwise, the prudent course is a period of postoperative airway protection and support with mechanical ventilation.

Postoperative disposition is dictated by the patient's clinical condition. The same considerations that bore upon the decision to extubate the trachea apply to planning for disposition. A patient who has had an uncomplicated operation and uneventful extubation may be managed in the recovery room and discharged to the hospital floor. Intubated patients and those with important postoperative concerns should be managed in an intensive care unit. Additionally, patients who have received large-bore central access for the hepatectomy may not be candidates for transfer to non-ICU settings, necessitating change or removal of the catheter used prior to discharge to the floor.

Analgesic requirements for patients after hepatic resection deserve careful consideration. Subcostal incisions are typically quite painful, and ineffective pain therapy will reduce the patient's ability to comply with postoperative pulmonary recruitment maneuvers and early ambulation. Regional anesthesia (eg, epidural catheter) added to general anesthesia provides superior early postoperative pain control.135 This must be balanced against the potential for postoperative hepatic synthetic failure and coagulopathy complicating subsequent removal of the epidural catheter. In 2 separate studies evaluating the use of epidural catheters in patients undergoing hepatectomy, 727 total patients safely received epidurals for perioperative analgesia without increased complications, although the use of epidural analgesia was related to an increased use of red blood cells in 1 study.136,137 Despite the potential risks, many practitioners opt to place the epidural catheter and monitor patients carefully for signs and symptoms of epidural hematoma.

Complications during Hepatic Resection

Intraoperative complications of hepatic resection can almost always be ultimately traced to excessive blood loss. Bleeding can result either from poor hemostatic control or coagulopathy. Coagulopathy rarely ensues during hepatic resection unless the patient had tenuous liver function at the start, the hemorrhage is severe, or patient warming has been inadequate. Reversible causes of coagulopathy should be sought and corrected and the circulating blood volume supported by infusions of crystalloids, colloids, and transfusion as appropriate.

Air embolism is another common complication. Air embolism during hepatic resection (as well as transplantation) is problematic because it alters pulmonary vascular resistance, right heart performance, and left heart filling. The pathophysiology of venous air embolism has been studied in dogs.138 Slow entrainment of air (ie, rates of 0.01-2.0 mL/kg/min), as might occur during surgery with small sites of venous opening, causes a progressive rise in central venous pressure, an early abrupt rise in pulmonary arterial pressure to a hypertensive plateau, and an unexplained decline in systemic vascular resistance. Air irritates the vascular endothelium, with resulting pulmonary edema, hypoxia, and reduced pulmonary compliance. Bolus infusion of air (ie, 1-13 mL/kg in a sudden bolus), as might occur with a major tear in the vena cava, causes increased central venous pressure. Because air fills the right ventricle, pulmonary and systemic pressures plummet, and cardiovascular collapse ensues.138

Air embolism is apparently a complication of many hepatic resections, although it is not always symptomatic. Some procedural approaches that may be advantageous from a surgical perspective may not be ideal from the anesthetist's viewpoint. For example, when comparing techniques for parenchymal dissection of the liver, the Cavitron ultrasonic aspirator (CUSA) is associated with less blood loss139 than a clamp-and-crush method. However, all CUSA patients had air emboli during hepatectomy, and in 44% of these, the air filled more than half of the right ventricle. Air emboli occurred in 68% of patients having clamp-and-crush hepatic resection as well, but to a much smaller extent. None of these emboli had pulmonary or hemodynamic effects on the patients, but this study suggests that air embolism is so common as to be considered ubiquitous during hepatic resection. Gas embolism from other commonly used devices, such as argon beam coagulators, has been described, in this instance with a fatal outcome.140

Air embolism is also problematic during liver surgery and transplantation because of the risk of catastrophic paradoxical embolism.141 Paradoxical embolism need not occur through an intracardiac right-to-left defect. Many patients presenting for hepatic resection (and certainly most liver transplant patients) have cirrhosis, and many cirrhotic patients have abnormal arteriovenous connections in the pulmonary circulation. Thus venous air embolism should be minimized to lower the risk of paradoxical embolus. Massive venous embolism and/or paradoxical embolus must be high on the differential diagnosis of unexplained cardiopulmonary performance problems during hepatic resection. Figure 57-7 shows the hemodynamic consequences of a large venous air embolism during a liver transplant. The first indication is an abrupt fall in end-tidal CO2 (black trace), followed a few moments later by rising pulmonary artery pressure (yellow trace). Systemic hypotension ensued (red trace). Inferior and lateral (see inset) ST-segment elevations accompanied systemic hypotension, caused either by coronary hypoperfusion or by air in the coronary circulation. The circuit gas composition (green trace) was changed to 100% oxygen to minimize the size of the gas bubbles. Cardiac output (orange rectangles) fell by 50% after the embolus.

Some practitioners recommend conducting hepatic surgery with the OR table in a 15-degree head-down tilt to prevent embolized air from migrating cephalad,142 but this may interfere with surgical exposure and may contribute to head and neck edema. If air embolism occurs, ventilation with 100% oxygen should be instituted. In severe embolism, placing the patient in the left lateral decubitus position with the head down may shift the gas bubble away from the right ventricular outflow tract and restore cardiac output. A central line placed into the right atrium can be used to aspirate gas from the heart. These measures must be undertaken while other supportive measures, including cardiopulmonary resuscitation (CPR) and fluid/pressor administration, are being continued. Cardiopulmonary bypass has been used successfully in resuscitation from gas embolism and should be considered if initial measures are unsuccessful.143

Indications, Contraindications, and Patient Characteristics

The indications for liver transplantation are myriad in detail (Box 57-8) but all come down to liver failure sufficiently severe to preclude further survival without transplantation.

The most common indication for liver transplantation is chronic hepatocellular disease due to alcohol and/or hepatitis. Hepatitis C is an increasingly important indication for liver transplantation, representing a unique and growing health risk for anesthesiologists who provide care for these patients. There is currently no vaccine against hepatitis C, and medical therapy is suboptimal. Thus the most effective protection from the disease is to avoid exposure.

Hepatitis B and C both predispose patients to hepatocellular carcinoma. As the prevalence of hepatitis C in the population increases, so does the incidence of hepatocellular carcinoma. Thus this tumor is becoming increasingly common as an indication for liver transplantation.

As surgical techniques, risk stratification of potential recipients, and the management of intercurrent diseases (eg, HIV infection) all improve, the contraindications to liver transplantation are becoming more nuanced. For example, advanced age is not necessarily considered a contraindication to transplantation. Instead, elderly patients are assessed using sophisticated testing of cardiopulmonary performance and rigorous assessment of nutritional status, body mass index, and exercise tolerance. Box 57-9 provides a general list of contraindications to liver transplantation, but each patient must be evaluated as an individual with many extenuating and complicating factors considered.

Patients with fulminant hepatic failure require particular attention, as their status with respect to contraindications to transplantation may change on a daily or even hourly basis. As mentioned previously, acute infection is common in patients with fulminant hepatic failure but should be actively sought (or at least there should be a high index of suspicion) in any candidate who is high on the recipient list because acute infection is a clear contraindication to transplantation. Brain herniation (portending brain death) is another clear contraindication to transplantation. In critically ill, comatose transplant candidates, herniation is always a possibility, yet transplantation may avert this disastrous outcome. Incipient brain herniation is commonly assessed by serial head computed tomography (CT) or, ideally, by intracranial pressure monitoring, so that donor organs are not mistakenly allocated to patients who can no longer benefit from them. However, many neurosurgeons are reluctant to place intracranial pressure monitors because of the risk of hemorrhage (see above).

Patient Selection for Liver Transplantation

Liver transplantation is an arduous process before, during, and after the operation. Part of the evaluation aims to identify individuals who can comply with lifestyle requirements needed to maintain the health of the grafted organ. Recipients must be able to sustain lifelong abstinence from alcohol, illicit drugs, and diverted prescription narcotics. Lifelong immunosuppression is also a requirement, and patients must have the means to obtain these necessary drugs and the personal organization and/or social supports to follow the complex medication regime.

Evaluation seeks to identify individuals with sufficient psychologic resilience, insight, and social supports who will be able to benefit over the long term from a resource as scarce as donor livers. Thus liver transplant listing committees are made up not only of surgeons and hepatologists, and, ideally, anesthesiologists, but also psychiatrists, addictions specialists, social services specialists, family therapists, and financial assistance experts.

Potential liver transplant recipients must be willing to accept massive blood transfusion during and after surgery. This requirement, formerly absolute, is relaxing as some centers gain sufficient expertise to reliably perform liver transplantation with little or no requirement for transfused blood. For example, Jehovah's Witnesses were formerly excluded from orthotopic liver transplantation candidacy unless they were willing to accept blood product transfusion. The first case reports of successful transplants occurred in 1996,144,145 and since that time, increasing numbers of these patients have undergone successful transplantation in multiple centers willing to offer transplantation to Jehovah's Witnesses who refuse transfusion.146,147 It should also be noted that Jehovah's Witnesses are allowed some latitude regarding their choice to receive or refuse transfusion, although the ultimate choices are personal ones made by the patient.

Potential recipients must be in the best possible physical condition within the context of hepatic failure and end-stage liver disease. For example, many programs require obese potential candidates to lose weight because obesity (body mass index [BMI] >30) is associated with excess mortality in the perioperative period.148 A BMI greater than 30 is considered a relative contraindication to transplantation.

Model for End-Stage Liver Disease (MELD) Scoring System

The United Network for Organ Sharing (UNOS; www.unos.org) administers the allocation of donated organs in the United States. Liver transplant recipient candidates are priority ranked by application of the MELD scoring system. The MELD system ranks patients by expected mortality based on the severity of their liver disease. An analogous system for pediatric patients, the Pediatric End-Stage Liver Disease (PELD) scoring system, is applied for patients younger than 12 years of age. Thus the MELD and PELD scores provide a way to rank patients in descending order of severity of disease (as reported by the likelihood of death from untreated disease), with higher scores indicating more severe disease burden.

The MELD scoring system uses a multivariate regression model to calculate a risk of death from the patient's liver disease based on the prognostic factors (laboratory values reflecting hepatic synthetic and excretory function) and regression coefficients (Table 57-1). Patients are assigned a MELD score based on the following calculation:

Scores are rounded to the nearest whole number. Thus the risk score of a hypothetical patient with cirrhosis who has a serum creatinine concentration of 1.9 mg/dL, a serum bilirubin concentration of 4.2 mg/dL, and an INR value of 1.2 would be calculated as follows:

Recognizing that the MELD score does not fully encompass the unique characteristics of patients needing liver transplantation, UNOS defines several exceptions and modifications to the MELD system. For example, patients with hepatocellular carcinoma receive additional MELD points, improving their likelihood of receiving a transplant. Similar adjustments are made for adult patients with hepatic metabolic syndromes. MELD exception points are also granted to patients with hepatopulmonary syndrome, with additional MELD points given to patients with documented PaO2 less than 60 mm Hg and stratified by the degree of hypoxemia with increasing severity given increased MELD credit.149 Finally, patients with acute liver failure can receive a special listing status—Status 1A—that puts them at the top of the waiting list. A candidate can be listed as Status 1A if he or she has fulminant liver failure with a life expectancy without a liver transplant of less than 7 days, as defined by these 4 categories:

1. Fulminant hepatic failure defined as the onset of hepatic encephalopathy within 8 weeks of the first symptoms of liver disease. The absence of preexisting liver disease is critical to the diagnosis. One of 3 criteria must be met to list an adult patient, who must be in the ICU, with fulminant liver failure: (1) ventilator dependence, (2) requiring dialysis or continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVD), or (3) INR greater than 2.0, or

2. Primary nonfunction of a transplanted liver within 7 days of implantation; as defined by (a) or (b):

   1. (a) AST of 5000 or greater and one or both of the following:

      • An INR of 2.5 or greater
      • Acidosis, defined as having a pH of 7.3 or lower and/or lactate greater than or equal to 2 times normal

   2. (b) Anhepatic patient, or

3. Hepatic artery thrombosis in a transplanted liver within 7 days of implantation, with evidence of graft failure as defined in 2(a) and 2(b) above; or

4. Acute decompensated Wilson disease

Status 1 patients accrue additional points for time spent waiting for an organ in that status. There are separate waiting lists for each major blood group. To ensure the fair allocation of livers, adhering to the system is mandatory throughout the United States. Similar systems are in place throughout the developed world.

When a donor organ becomes available it is offered to transplant programs in the following order of priority:

1. The organ is offered to Status 1 patients (in descending point order) in the same local area as the procuring center.

2. The organ is offered to transplant programs with Status 1 patients (in descending point order) in the same organ-sharing region as the procuring center.

3. The organ is offered to candidates with MELD/PELD Scores 15 or higher in descending order of MELD/PELD scores, first locally and then regionally.

4. The organ is offered to patients with MELD/PELD scores of less than 15, locally and then regionally.

If no transplant program has accepted the organ by the end of this list, then it is offered at the national level, first to the Status 1 patients in rank order and then down the MELD/PELD waiting list.

Preanesthetic Evaluation of the Liver Transplant Candidate

Because of the prescreening process for listing a patient for liver transplantation, most patients are "well studied"—that is, they have had an extensive prior diagnostic and risk stratification assessment. Thus, on the day of surgery, the immediate preoperative evaluation of the patient for liver transplantation focuses on the history and physical examination relevant to the case immediately at hand and any changes that may have occurred since the patient's last evaluation. Furthermore, although technically elective surgery, liver transplantation is an unscheduled, urgent case with many surgical teams, recipient patients, and hospitals throughout the region preparing for synchronous receipt of donor organs. Thus efficient and effective immediate preoperative care of the potential liver recipient is beneficial, both to the patient and to the medical system in general.

A typical preanesthetic history is taken, with attention to a few key points. Specific questioning pertinent to liver transplantation covers a variety of topics:

• Because liver transplants are unscheduled, the patients are rarely fasted. However, the quality and quantity of recent oral intake helps define the risk and potential consequences of regurgitation and aspiration of gastric contents. This often does not affect the anesthetic induction plan, as these patients are usually considered as "full-stomachs" and as such, warrant rapid sequence induction of general endotracheal anesthesia.
• Liver transplantation requires ample vascular access for resuscitation and monitoring. A history of previous central venous and/or arterial catheter placement will alert the anesthesia team to possible difficulty with access due to occluded vessels, although in practice, ultrasonography used in catheter placement also shows vessel patency.
• Questions should also be directed to assess hepatic synthetic function, which may have deteriorated further since the patient's last reevaluation. A history of increasing abdominal girth or peripheral edema indicates failure to synthesize sufficient albumin and other plasma proteins to maintain plasma oncotic pressure. A history of easy bruising, bleeding during oral hygiene, or prolonged bleeding from minor injuries indicates insufficient hepatic function to maintain clotting factor levels at even a fraction of normal levels.
• The history should address neurologic status, searching for evidence of worsening encephalopathy, manifesting itself as loss of mental acuity, forgetfulness, fatigue, and somnolence. It is also important to characterize and document any preoperative focal neurologic deficits to establish the patient's status prior to the case. Positioning injuries with consequent neurologic deficits are not uncommon. It is useful to know, when a patient complains of a deficit in the postoperative period, whether that deficit was present prior to surgery.
• The anesthesia team should reassess cardiac risk during the history, as many orthotopic liver transplant candidates wait for months or years between rescreening tests of cardiac function and ischemic risk. It may be difficult to decide whether decreasing exercise tolerance is attributable to cardiac dysfunction or worsening liver disease, so symptoms or signs of angina should be sought. Additionally, documentation of portopulmonary hypertension or hepatopulmonary syndrome should be sought, and this information could alter the anesthetic plan or cancel the surgery if PA pressures are elevated, uncontrolled, and/or untreatable in the time frame of the perioperative period.
• Renal function should likewise be reviewed, as worsening renal function secondary to disease progression or concomitant hepatorenal syndrome may warrant intraoperative or postoperative hemodialysis.

The physical examination should be as complete as that conducted for any patient undergoing major intra-abdominal surgery. Special attention should be paid to the assessment of ascites. Ascites potentiates the possibility of regurgitation and aspiration. It also compromises pulmonary performance and may prevent the patient from being able to breathe while supine for central venous catheter placement. Finally, ascites pushes the diaphragm upward, causing atelectasis and diminishing the functional residual capacity. Thus ascites predisposes liver transplant patients to rapid and severe desaturation during induction of anesthesia, even after assiduous denitrogenation.

Attention should also be paid to sites for vascular access. Large-bore (ie, 14 gauge or 8.5 French) venous cannulae are essential for volume resuscitation during the case, and these must be above the diaphragm, as the inferior vena cava will be cross-clamped at times. A femoral arterial catheter for pressure monitoring may be useful (see below). Landmarks for internal and external jugular cannulation, as well as subclavian access, should be examined, as well as peripheral venous and arterial sites on both arms.

Diagnostic Studies in the Liver Transplant Candidate

Laboratory tests obtained in the immediate preoperative period should include measures of hepatic synthetic and excretory function, and should specifically include serum albumin and bilirubin. Routine coagulation studies (PT, PTT, fibrinogen, and platelet count) give a measure of how hepatic synthetic failure has affected clotting factor levels. The platelet count can be low in the case of portal hypertension, as platelets are sequestered in the enlarged spleen.

Preoperative measurement of serum electrolytes is essential to provide baseline data about possible hyponatremia, hypo- or hyperkalemia, hypocalcemia, and hypomagnesemia. BUN and creatinine concentrations should be measured to assess the patient's renal function, which may in turn presage poor platelet function if uremia is present. This assessment of renal function (and acid–base status; see below) guides the possible use of intraoperative renal replacement therapy. Although rarely required, intraoperative renal replacement therapy may be needed if significant renal failure, electrolyte abnormality, or acid–base problems are found in the immediate preoperative laboratory investigation.

Hemoglobin should be measured to establish the preoperative baseline oxygen-carrying capacity. The patient's blood type should be redetermined, and a sample sent to the blood bank for antibody screening in anticipation of allogeneic transfusion. An electrocardiogram should be obtained in the immediate preoperative period to search for new changes suggestive of coronary artery disease. Finally, a preoperative chest x-ray is obtained as a baseline for comparison of postoperative films.

Patients presenting for liver transplantation almost always have an extensive body of laboratory and diagnostic test results available to aid in perioperative risk assessment and anesthetic planning. Patients with acute liver failure may be exceptions to this generalization, being listed for transplantation and subsequently receiving grafts within a few days of their initial presentation.14 This may also be true of patients previously evaluated as transplant candidates but moved up on the transplant list due to an abrupt worsening of their MELD score. However, in almost all cases, the following assessments are either repeated upon admission for transplantation or have been performed within the prior year.

Laboratory assessment of pulmonary function includes arterial blood gas measurement and pulmonary function testing. Blood gas measurement identifies patients with hypoxia, suggesting hepatopulmonary syndrome. Pulmonary function testing often reveals small lung volumes reflecting the effect of ascites. In patients with a long history of smoking, there may be a superimposed obstructive pattern on spirometry. These results are important, as the liver transplant patient is mechanically ventilated for a prolonged intraoperative period and perhaps for some time in the postoperative period.

Cardiac assessment of the patient being considered for liver transplantation focuses on functional and invasive tests of cardiac performance that assess ischemic potential and the search for cardiac structural anomalies that might compromise outcome from orthotopic liver transplantation.150

The incidence and severity of coronary artery disease increases with age and with well-known risk factors, many of which are commonly found in patients with liver failure such as diabetes, smoking, and obesity. Furthermore, better surgical and anesthetic techniques are allowing older patients—that is, patients with greater age-related risk of significant coronary disease—to be considered for liver transplantation. Flow-limiting coronary artery disease is of grave concern because liver transplantation is still a highly stressful operation. The potential for sudden, massive, and ongoing blood loss complicated by extreme electrolyte derangements is still present, so all potential liver transplant recipients must be evaluated as if they will be required to tolerate minutes to hours of a hypothetical state with a heart rate above 110 beats/min and a mean arterial pressure of less than 50 mm Hg, with a hemoglobin of 7 g/dL and a pH under 7.2. Only patients with ideal cardiac status are likely to survive this scenario unscathed.

To ensure that new and previously listed transplant candidates meet these criteria, the liver transplant anesthesia team periodically reviews the preoperative evaluation of individuals high on the liver transplant list. This task involves reviewing the echocardiogram, the results of functional stress testing, and, if performed, cardiac catheterization results. This is not an academic exercise, as a significant fraction of patients being evaluated for liver transplantation have coronary artery disease, and the coronary disease of many of these patients was unsuspected prior to pretransplantation evaluation. For example, in a study applying coronary angiography to all potential liver transplant recipients older than 50 years of age, there was a 27% incidence of moderate to severe coronary artery disease, with 13.3% of the cohort having clinically unsuspected moderate or severe coronary disease.151 Another study showed an incidence of 5.6% for coronary artery disease in patients older than 40 years of age,152 and the consensus seems to be that about 2.5% to 10% of patients have moderate to significant coronary artery disease.153 Untreated significant coronary disease is potentially lethal in the setting of liver transplantation.150 In 1 study, half of all patients with coronary artery disease who underwent liver transplantation died in the perioperative period, and the morbidity rate was 81%.154

It appears that dobutamine stress echocardiography or possibly exercise stress thallium imaging is the best screening test in patients with end-stage liver disease.153,155-157 A recent meta-analysis indicates that dobutamine stress echocardiography has a superior negative predictive value in patients having elective noncardiac surgery.158 Dobutamine stress is commonly used in pretransplant evaluation because it is considered to most closely mimic the state commonly found during liver transplantation and in end-stage liver disease.155 A negative dobutamine stress echocardiogram with adequate stress appears to predict a favorable perioperative cardiac outcome.156,159 It is important to achieve at least 85% of the predicted maximal heart rate so that the dobutamine stress echocardiogram is diagnostic. Otherwise the diagnostic value of the test is compromised.160 However, a recent retrospective analysis of OLT patients who underwent both dobutamine stress echocardiography and coronary angiography prior to their transplants showed that in patients who did achieve target heart rates, dobutamine stress echocardiography had a low sensitivity (13%) and a low positive predictive value (22%), questioning the accuracy of stress echocardiography in this population and the possible need for an alternative method of cardiac risk stratification.161

In the hyperdynamic state produced by the dobutamine stress echocardiography protocol, a significant number of patients develop a dynamic left ventricular outflow tract obstruction. However, despite the fact that more patients with dynamic left ventricular outflow tract obstruction developed intraoperative hypotension at transplantation, the overall outcomes (mortality) were the same between patients with obstruction and those without.162

Most transplant programs use a cardiac risk stratification schema similar to that devised by Plevak155; the version used by our program, for example, is shown in Fig. 57-8.

The ideal management of potential liver transplant recipients with significant coronary disease is a difficult problem with little evidence to guide decision making. Patients with end-stage liver disease who undergo coronary artery bypass grafting have significant morbidity. For example, in 1 study, patients with cirrhosis who underwent coronary artery bypass grafting had a 58% incidence of morbidity and significant complications.163 Even patients with relatively mild liver disease (Child class A and B liver disease) who underwent coronary artery bypass grafting had extremely high mortality and morbidity.164 The benefit of an intervention, such as coronary angioplasty, stenting, or atherectomy, has not been formally studied on a large scale to show outcome compared with coronary artery bypass grafting.153 Small series have reported good results with combined orthotopic liver transplantation and coronary artery bypass grafting,152,165,166 but at present, such a combined procedure is considered heroic in most transplant centers.

Independent of ischemic coronary artery disease, many patients with end-stage liver disease have a poorly understood disorder known as cirrhotic cardiomyopathy (a different entity from alcoholic cardiomyopathy) despite supranormal cardiac outputs.30 This condition is multifactorial, and its mechanisms may include impairment of the β-adrenergic system, nitric oxide (overproduced in liver failure), cytokines, and the prolonged hyperdynamic circulation.167 Many patients with apparently normal ventricular function prior to surgery develop left ventricular failure in the postoperative period.33,159 These patients, representing 1% to 6% of liver-transplanted individuals, may have had occult cirrhotic cardiomyopathy. Unfortunately, prospective diagnostic criteria for cirrhotic cardiomyopathy are lacking, although a recommendation made at the 2005 World Congress of Gastroenterology in Montreal suggested that a classification system of cirrhotic cardiomyopathy includes systolic and/or diastolic dysfunction in response to stress in the absence of any preexisting cardiac disease.168

All patients being considered for liver transplantation should undergo a screening transthoracic echocardiogram. This is a good screening test to search for cardiac structural abnormalities as well as anomalies of the surrounding vasculature. It is also an important test to exclude portopulmonary hypertension.

Cardiac structural anomalies can affect outcome by impairing cardiac performance intraoperatively (eg, functional or fixed valve stenoses) or by allowing passage of emboli from the right to the left side of the heart. Patent foramen ovale (PFO) and other septal defects may be a significant risk to orthotopic liver transplant patients and patients undergoing hepatic resection when fixed or transient right-to-left shunting occurs. Right-to-left shunt increases the possibility of paradoxical embolus of clot, air, or debris. Hepatic surgery can lead to large openings in the inferior vena cava, so the embolization problem can be severe. In fact, in 2 series, between 1% and 6% of all patients undergoing orthotopic liver transplantation had thrombus detected in the right heart.169,170 Because roughly 25% of all hearts in unselected autopsy subjects have PFOs171 the risk of injury due to paradoxical embolism may be greater than currently appreciated. On the other hand, in a recent study evaluating the risk of hepatic transplant patients with patent foramen ovales, 27 patients with patent PFOs were compared to 61 non-PFO transplant patients, and both perioperative outcomes and 30-day mortality rates were similar in both groups.172 This does not prove that PFO patients are not at elevated risk. Their anesthesia and surgical teams might simply have avoided accidental emboli better. Therefore, in preparation for elective hepatic surgery and certainly in the evaluation for orthotopic liver transplantation, cardiac septal defects should be sought by echocardiography or magnetic resonance imaging (MRI).

Transthoracic echocardiography can be used to interrogate the intra-atrial septum using color-flow Doppler mode. Additionally, bubble contrast echocardiography is a highly sensitive test for septal defects. Early passage (within 1-2 beats) of air from the right to the left heart indicates a septal defect, whereas later arrival of air on the left side indicates intrapulmonary shunting. This latter finding cannot be remedied, but when atrial defects are detected, consideration should be given to closing them before transplantation.

Closure of patent foramen ovales prior to orthotopic liver transplantation is controversial, although it can now be accomplished percutaneously.173 No controlled studies evaluating the usefulness of this intervention have appeared. Factors favoring closure are (1) embolism is common, particularly during the reperfusion period; (2) right heart dysfunction with right heart pressures greater than left heart pressures is common during reperfusion; and (3) paradoxical embolism occurs in this setting.174 On the other hand, the relationship between the presence or size of a patent foramen ovale and the likelihood of paradoxical embolus has not been clearly established. Although there are case series of paradoxical embolism documented by transesophageal echocardiography during liver transplantation,174 it is not clear whether these necessarily occur through a patent foramen ovale. Furthermore, closing a patent foramen ovale commits the coagulopathic patient with liver disease to months of antiplatelet agents.

Magnetic resonance imaging has recently been applied to the assessment of the intra-atrial septum. Small studies comparing this technique with color-flow Doppler echocardiography and bubble contrast studies indicate that MRI has similar sensitivity and specificity to these echocardiographic techniques.175

The final cardiopulmonary problem to be investigated in the prelisting evaluation is portopulmonary hypertension, the management of which has been described previously. Figure 57-1 outlines the diagnostic and therapeutic decision approach to portopulmonary hypertension. Portopulmonary hypertension occurs in 2% to 4% of patients with end-stage liver disease and 5% to 10% of patients being evaluated for orthotopic liver transplantation.53 The clinical predictors of pulmonary hypertension in liver transplantation include systemic hypertension, right ventricular dilation by echocardiography, estimated pulmonary artery systolic pressure of 40 mm Hg or greater by transthoracic echocardiography, right ventricular hypertrophy by echocardiography, or a right ventricular heave.176 The mortality associated with pulmonary hypertension during liver transplantation is significant. Half of the patients with mean pulmonary pressures between 35 and 50 mm Hg died in the peritransplant period, and mortality was 100% in those with mean pulmonary artery pressure greater than 50 mm Hg.177 These results are similar in a multicenter retrospective review,58 leading many centers to deny orthotopic liver transplantation to patients with more than mild portopulmonary hypertension. However, in some centers, mild portopulmonary hypertension (ie, mean pulmonary artery pressure <35 mm Hg with good ventricular function) is not associated with poor early or late outcomes.178 A retrospective study examining outcomes in portopulmonary hypertensive patients demonstrated 5-year survivals of 14%, 45%, and 67% for patients in 3 subgroups, respectively, who had (1) no therapy or liver transplantation alone, (2) only therapy for portopulmonary hypertension, or (3) therapy for portopulmonary hypertension followed by liver transplantation.179

Transesophageal echocardiography is rarely indicated in the preoperative assessment of orthotopic liver transplantation candidates. The procedure may require sedation, which can be complicated in the patient with end-stage liver disease. Furthermore, there is the risk of disrupting esophageal varices during the examination.

Operative Approaches for Liver Transplantation

Liver transplantation is conveniently divided into 3 phases: the preanhepatic phase, the anhepatic phase, and the neohepatic or reperfusion phase. During the preanhepatic phase, a complete hepatectomy is performed. During the anhepatic phase, vascular anastomoses between the donor liver and the recipient's vessels are constructed. During the neohepatic phase, the hepatic arterial and biliary anastomoses are constructed, and the wound is closed.

A liver transplant begins like a hepatic resection, using the same incision and exposure and imposing the same hemodynamic consequences. The surgeon exposes and gains control of the hepatic vasculature. The hepatic artery, portal vein, and the common bile duct are clamped and divided. Two different techniques are commonly used for controlling hepatic venous outflow and constructing this anastomosis: (1) an en-bloc technique in which part of the recipient's vena cava is resected and replaced with a section of the donor vena cava, or (2) a "piggyback" technique in which the recipient vena cava is clamped with a side-biting clamp and a side-to-side anastomosis is constructed to the donor liver venous outflow. The choice of technique has important implications for anesthetic management and the expected course of the case, as described in the following.

In the en-block resection technique, the inferior vena cava must be clamped above and below the liver, with consequent severe reduction in venous return to the heart. Because both the portal vein and the inferior vena cava are clamped, the entire body below the caval cross-clamp, as well as the abdominal viscera, suffers venous congestion and ischemia unless an alternate route of venous return can be established. This massive loss of venous return, coupled with the insult of recirculating blood from such a large ischemic territory at the time of reperfusion, leads to profound hemodynamic instability requiring pharmacologic intervention, sudden hypothermia at reperfusion, and elevated potential for malignant cardiac arrhythmias. These difficulties have motivated the development and routine use of venovenous bypass techniques. This is commonly achieved via venovenous bypass from the lower half of the body to a great vein draining into the superior vena cava (Fig. 57-9).

Venovenous bypass may be used to decompress the lower systemic venous circulation, the portal circulation, or both. The advantages and disadvantages of venovenous bypass have been reviewed.180 Without the preserved venous return afforded by venovenous bypass, the cardiac output and blood pressure may fall dramatically; often the cardiac output falls by more than 50%. Such falls in cardiac output are suggested to increase morbidity and mortality,180 although primary research has failed to detect this association.181,182

Failure to decompress the lower systemic and portal venous systems leads to severe venous congestion below the caval cross-clamp. Above the clamp, reduced venous return reduces left ventricular preload and cardiac output, with a net result of reduced perfusion pressure for organs below the caval cross-clamp. Thus, without venovenous bypass, renal venous pressure is elevated, systemic arterial pressure is depressed, and renal perfusion pressure is degraded. Thus venovenous bypass might be expected to afford some protection from renal failure in the perioperative period, but the net effect on renal function is equivocal. For example, venovenous bypass is not associated with improved postoperative renal function relative to matched patients whose liver transplant was performed without bypass.183

First described in 1984,184 venovenous bypass is a technique wherein blood is actively pumped using a centrifugal pump from large-bore drainage cannulae to a similarly large return line (Fig. 57-10). These can be inserted percutaneously or via a cut-down procedure. A common drainage site for the lower systemic venous circulation is the left femoral vein. The portal vein, if drained, is accessed from the surgical field. Common return sites are the right internal jugular and left subclavian veins via percutaneous access or the left axillary vein via a cut-down technique.

Percutaneous insertion of the bypass cannulae may be performed by the surgical team or by the anesthesia team at the beginning of the case. An alternative approach is to prep the left groin and axilla for possible cut-down access and then defer access until it becomes clear that venovenous bypass is needed. Percutaneous access appears to be quicker and to provide better flows,185,186 but the cut-down technique persists. The bypass cannulae are very large, and when placed percutaneously, require multiple passes with successively larger sharp, stiff dilators passed over a stiff guidewire to create a large enough skin entrance, as illustrated in Fig. 57-11.

Assiduous care should be taken to pass the dilators only deep enough to enlarge the skin punctures, and under no circumstance should the tip of any dilator be allowed to pass beyond the end of the guidewire. Exsanguinating hemorrhage into the chest and cardiac tamponade from cardiac puncture have occurred as mishaps of venovenous bypass cannula placement.187 Extreme care should be taken to facilitate reliable cannulation of the target vein, including the possible use of ultrasonography to guide initial venous access and manometry to confirm venous placement using a small, temporary catheter prior to beginning dilation. A postinsertion chest x-ray to confirm vascular placement and correct insertion depth is mandatory prior to initiating venovenous bypass.

The bypass circuit should be carefully cleared of air as connections are made, and all connections should be secured prior to initiating bypass. Systemic heparinization is not performed, as the bypass circuit is heparin bonded.188 Bypass flow rates of 1.5 to 5 L/min are typical. The initiation of bypass is a critical period, as malplacement of the return line becomes apparent with disastrous consequences almost immediately. For example, accidental placement of the tip of the return line through a cardiac chamber wall and into the pericardial sac will lead to near-instantaneous, severe cardiac tamponade with initiation of flow. Fatal air embolism has occurred due to connection failure during venovenous bypass, so the pump and its circuit require constant attention by dedicated, specialized personnel.

Despite the improved conditions afforded during surgery, it is not clear that venovenous bypass improves long-term outcomes. Because of the potential for complications, coupled with improvements in surgical techniques (see below) some have questioned the usefulness of routine venovenous bypass.180

The alternative approach to liver transplantation, the vena cava preservation (or "piggyback") technique,189 is designed to preserve vena cava flow for all but a few minutes of the transplant procedure. Portal venous and hepatic arterial control is obtained as above. Instead of a cross-clamp, a "side-biter" clamp placed on the inferior vena cava isolates the liver from the systemic venous system. Figures 57-6 and 57-12 illustrate this clamping method. In Fig. 57-12, a button of vena cava with the hepatic vein attachments has been removed, and the hole is held closed by the side-biter clamp at the bottom of the wound. The vena cava deep to this clamp is largely open to flow. This allows venous return from the lower systemic but not the portal venous system. Frequently, a brief period of total venous occlusion with a vena cava cross-clamp is needed to position the side-biter clamp. Vena cava distension due to overzealous volume replacement during the hepatectomy can make the piggyback technique more difficult for the surgeons. Because exposure for the hepatectomy is more difficult and the anastomosis is more complicated, the piggyback technique may take longer to perform. However, many programs now use this technique almost exclusively.190

Piggyback transplantation is associated with a lower incidence of renal failure,191 better gas exchange, and better acid–base status at reperfusion,192 as well as better intraoperative hemodynamic stability. A retrospective, 3-year analysis of 426 liver transplantations utilizing either retrohepatic caval resection with venovenous bypass, piggyback technique with venovenous bypass, or piggyback technique without venovenous bypass demonstrated that the piggyback-only technique utilized the smallest amount of blood products, had the lowest incidence of renal failure, and had overall better patient and graft survival when compared to the other 2 techniques.193 Additionally, this technique results in little to no need for venovenous bypass, as demonstrated in a series of 500 liver transplantations in which the piggyback technique was utilized and no patients required venovenous bypass in order to maintain hemodynamic stability.194

Failure to decompress the portal system may lead to splanchnic congestion unless the recipient has large portosystemic shunts. Nevertheless, the piggyback technique reduces the transfusion requirement as well as the need for vasoactive drugs during the completion of the hepatectomy and construction of the venous anastomoses.195 Temporary portocaval shunts have been described in association with the piggyback technique. The temporary shunt appears to improve intraoperative hemodynamics and reduce transfusion requirements,196 but is not widely used. In general, use of the piggyback technique dramatically reduces the severity of problems during the anhepatic and reperfusion stages of the operation.

As the hepatectomy is being completed, a separate surgical team prepares the donor liver for implantation, working at a separate table. The graft vessels are trimmed to fit their counterparts in the recipient. Next, the graft is brought to the recipient surgical field, and the vascular anastomoses are constructed. The surgical goal during this phase of the operation is to construct patent, nonleaking anastomoses as efficiently as possible to minimize the warm ischemic time of the liver. Thrombosis of the recipient portal vein is a relatively common finding, either during the dissection or at the time of initial graft reperfusion. When discovered, portal venous thrombosis typically prompts an attempted thrombectomy using Fogarty catheters, a potentially bloody process. Typically, the donor hepatic to recipient vena cava and the donor portal to recipient portal venous anastomoses are constructed, flushed, and opened as quickly as possible to establish a circulation in the graft. Then the hepatic arterial anastomosis is constructed, flushed, and opened, completing the graft blood supply.

Finally, a biliary drainage is constructed. This may either be by direct anastomosis of the graft bile duct to the recipient common bile duct or via a Roux-en-Y construct using the jejunum.

Anesthesia for Liver Transplantation

Concerns and activities during anesthesia for liver transplantation mirror the major phases of the surgery. The anesthesia can thus be roughly divided into the following phases:

• Preinduction
• Induction, preparation for surgery, and maintenance
• Preanhepatic phase
• Anhepatic phase
• Venous reperfusion of the graft
• Neohepatic phase
• Emergence/transport to ICU

The anesthesia team attends to multiple homeostatic goals throughout the case (Table 57-2). Liver transplant anesthetics are some of the most complex currently performed because of the surgical and medical criticality of the patients and because of the complexity of the equipment required to perform the case.

Figure 57-13 is a panorama from the anesthesiologist's perspective during a liver transplant. Multiple user interfaces, cables, monitoring lines, and infusions must be well organized and systematically set up to make the cognitive load from the equipment acceptable and predictable so that the anesthesiologist can attend properly to the patient and the operation. Liver transplantation consumes tremendous resources. Most programs responding to a recent survey reported assigning at least 2 anesthesiology personnel and at least 2 additional professional personnel (ie, perfusionist, monitoring nurse, auto-transfusion nurse) to each case.197 Thus, in addition to the complexity of the equipment, team leadership, communication, and delegation of responsibility must be considered and managed during the case.

During the preinduction phase, the final evaluation of the patient is performed. Although there is unlikely to be any doubt about the identity of the patient and the operation to be performed, the anesthesia team must independently confirm the patient's identity, the operation to be performed, the recipient's blood type, and any allergies. Last-minute laboratory results should be reviewed. It is always prudent for a member of the anesthesia team to personally consult with the blood bank about the upcoming liver transplant so that it may prepare for a possible heavy demand for blood products. This is particularly true if the patient has developed antibodies to allogeneic red blood cells from previous transfusions, presenting an added challenge to the blood bank.

Close communication with the graft harvest team is essential to best sequence the activities with the donor to minimize graft ischemic time while at the same time minimizing the recipient's exposure to risks of anesthesia and invasive monitoring. Thus one might obtain initial peripheral intravenous (IV) access and then wait to place any additional monitors or vascular access until confirmation that the graft is suitable. In most situations, graft suitability is known at least 1 hour before the need to start the recipient's surgery, leaving ample time for induction of anesthesia, placement of central venous or pulmonary artery catheters, positioning of the patient, application of warming devices, and the initial surgical prep and drape.

Most patients with end-stage liver disease have at least some encephalopathy. Thus it is prudent to dose sedative premedications, such as benzodiazepines and opioids, judiciously, giving small doses and monitoring closely for desired and undesired effects.

Monitoring for liver transplantation relies on standard monitors plus invasive monitors directed toward the likely areas of additional concern during the case. Central venous pressure monitoring is often needed to assess intravascular volume status, as well as to goal-direct low CVP technique when utilized. Additionally, central venous catheterization provides large-bore transfusion access, allows passage of a PA catheter if needed, and provides a conduit for central vasopressor administration. Thus placement of a central venous catheter for liver transplantation seems almost obligatory. However, central venous pressure monitoring gives much of the same information as provided by intraoperative transesophageal echocardiography (TEE), which could replace the intravascular monitor if another suitable route can be found for the drugs.

Pulmonary artery catheterization is carried out if left or right heart performance is in doubt, if problems with pulmonary hypertension are anticipated, and to distinguish hypotension due to hypovolemia or heart failure from that due to lack of peripheral vascular tone, especially if TEE is not utilized during the case. One type of pulmonary artery catheter also allows for A-V pacing. The pulmonary artery catheter allows one to follow cardiac output and stroke volume throughout the case. The initial cardiac output measurements typically confirm a hyperdynamic circulation, with cardiac outputs of 10 to 11 L/min frequently seen at rest in adult male patients with end-stage liver disease.

An arterial catheter is usually inserted to closely monitor blood pressure and to provide convenient access for frequent laboratory sampling. When compared with femoral arterial catheters, radial artery catheters may not reflect the true systolic pressure during the reperfusion phase of transplantation or during vasopressor administration.198 However, mean pressures measured in the radial and femoral arteries correlate well regardless of the phase of the case or vasopressor administration.198 Thus a radial arterial catheter is sufficient to guide the management of the mean pressure. In some centers, 2 arterial catheters are placed so that blood pressure monitoring may proceed without interruption during frequent arterial blood gas withdraws, or as backup in case of an arterial line failure.

Transesophageal echocardiography should be considered for assessment of cardiac performance during transplantation, either as an adjunct or in place of pulmonary artery catheterization, and for monitoring embolism of air or thrombus. Air embolism is common, and TEE frequently reveals such events. Transesophageal echocardiography is most useful for early detection of large embolic events, with the hope of minimizing their effect by virtue of early detection and removal of the source. It is also a useful tool to assess the effect both of embolic events and therapeutic interventions on cardiac performance.

It is also useful to consider level-of-consciousness monitoring (BIS™ or similar). Liver transplant patients may be very sensitive to anesthetics, requiring smaller doses than typical patients. Level-of-consciousness monitoring can thus be used to minimize exposure to anesthetic agents and their potential deleterious effects on the circulatory system while providing some assurance that the patient will not recall the surgery.

Vascular access for rapid volume replacement can either be peripheral or in the central circulation. The patient likely requires central venous access for vasopressor administration, so it is tempting to use this route for volume as well. However, it is important to isolate vasopressors from the main volume cannula, as fluid for resuscitation may be delivered under pressure, effectively stopping the vasopressors. Multilumen large-bore central venous catheters or multiple catheters at separate central venous sites provide the necessary isolation. Alternatively, peripheral vascular access (eg, multiple 14-gauge IV catheters or a rapid infusion catheter as described previously) may be established. It is important to have at least 1 dedicated cannula that can carry the maximum flow rate of the available rapid infusion device (see below).

Anesthetic Induction, Preparation for Surgery, and Maintenance

Because most patients with end-stage liver disease have ascites and/or have had sclerotherapy of lower esophageal varices, rapid-sequence induction is the norm, with cricoid pressure applied and with the patient in optimal position for laryngoscopy. Careful denitrogenation is important, as most end-stage liver disease patients have reduced functional residual capacity. In patients with poor cardiac function, a preinduction arterial line may be warranted. Vasodilation and encephalopathy make patients with end-stage liver disease sensitive to induction agents. Thus the induction dose of hypnotic drugs, such as propofol or thiopental sodium (Pentothal), should be reduced (eg, 1 mg/kg-1 of ideal body weight for propofol in a cachectic patient with encephalopathy). Some clinicians elect to sidestep this issue entirely by using an induction agent such as etomidate. Skeletal muscle paralysis is typically obtained with succinylcholine followed by a nondepolarizing agent, or with rocuronium at a dose sufficient for rapid-sequence induction.

Antibiotics targeted against skin flora (eg, cefazolin) should precede skin incision by no more than 60 minutes.199 Antibiotics should be redosed throughout the case to account for elimination and loss due to hemorrhage.

During maintenance of anesthesia, hepatic encephalopathy reduces opioid and anesthetic requirements. Thus it is possible to inadvertently administer relative overdoses of anesthetics by overestimating the patient's needs. Similarly, opioids may have enhanced potency and prolonged duration of action due to hepatic failure. On the other hand, massive hemorrhage and resuscitation can diminish the circulating opioid concentration. Thus it is appropriate to titrate intermediate acting opioids, such as morphine, hydromorphone, or fentanyl, to the patient's needs throughout the case. The choice of paralyzing agent should also be guided by the clinical situation. For example, agents requiring hepatic degradation are probably not optimal if early extubation is contemplated.

Positioning the patient requires special attention. Liver transplants are long cases with the potential for hypotension and consequent extremity hypoperfusion. Furthermore, surgeons may lean heavily on the patient to perform parts of the operation. Thus positioning injuries are possible, and great care should be taken to protect the patient by generously supporting and padding all of the body, either with compressible foam or viscoelastic gel. As surgical needs may warrant frequent changes in table position throughout the case, all extremities should be carefully secured. Pneumatic compression stockings are applied, and a urinary catheter is inserted.

The case is performed with the patient in supine position. If required, the right arm may be tucked alongside the patient's body to allow access for several surgeons. If so, the right arm is out of reach of the anesthesiologist, and no critical monitors or access devices should be placed there unless no alternative sites are available. In addition to problems with accessibility, devices placed in the tucked right arm may cause patient injury due to compression. Accordingly, we typically limit devices in the right arm to a single large-bore peripheral IV and arterial line. The left arm is abducted to facilitate access for venovenous bypass. Therefore, the left arm is also an ideal site for arterial monitoring and peripheral venous access. Venous access in the left arm may be occluded if venovenous bypass is instituted via cut-down to the axillary vein, but the bypass circuit has a separate high-flow inlet into which this infusion can be attached. Other sites of access include both femoral regions. Venous access below a potential vena cava cross-clamp is of little utility, either for monitoring or volume administration. Furthermore, the left femoral vein is typically reserved for possible venovenous bypass access. However, cannulation of the right femoral artery may be useful if a complicated case is anticipated. Both internal jugular veins are available with the patient in supine position. If required, dual large-bore catheters may be placed in a single internal jugular vein. Care must be exercised to ensure that the catheters are sufficiently separated along the axis of the vein to prevent forming a larger, single connected hole.

The entire abdomen and chest are prepped for surgery. Additionally, the left groin and axilla are included in 1 large, contiguous prep if venovenous bypass via open access is contemplated.

Patient warming becomes a major issue due to the extensive use of alcohol-based skin prep solutions over a large surface, the size of the incision, the duration of the case, and reperfusion of a cold graft. Hypothermia should be avoided because it negatively affects coagulation,121 resistance to infection,120 and the potential for early extubation. Warming strategies commonly focus on IV fluids and forced-air warming devices.

Forced-air warming is effective, although the extensive area exposed and prepped during liver transplantation makes finding sufficient surface area on which to apply warmers a challenge. A procedure involving the entire abdomen, as well as the left groin and axilla for establishment of venovenous bypass, leaves the head, left arm, and lower legs for warming. Forced-air warming blankets for underbody use, which presumably function by forming a warmed-air plenum under the drapes, are available and should be considered. These appear to be effective to the extent that they are not compressed and deflated by the weight of drapes and surgeons pressing against them. In this instance, we place forced-air warming blankets on all available sites, including under the patient. In our experience, patient temperature drops to about 36°C during induction, prepping, and draping; increases to 37°C during the preanhepatic phase; and then falls by approximately 1°C at hepatic reperfusion. Subsequently, the temperature increases to 37°C during the neohepatic phase, prompting the gradual discontinuation of forced-air warming to maintain normothermia. If lower-extremity forced-air warming is used, anesthesiologists must remember to cease use of these if aortic cross-clamping occurs at any time during the case, or thermal injury may result.

Warming intravenous infusions is mandatory, given the volume of refrigerated banked-blood products that will likely be transfused. Fluid warming for liver transplantation is usually achieved with commercially available high-flow warming devices. The ideal transfusion device has a reservoir to allow the user to establish a reserve of blood for sustained rapid infusion in the face of uncontrolled hemorrhage. The infusion flow rate should be reported. The device must contain an air detector that stops the infusion when air is detected in the patient limb of the circuit. Ideally the device contains a debris filter between the reservoir and the patient.

Three devices are in common use, and each has unique advantages and weaknesses. The characteristics of the 3 major rapid infusion systems are listed in Table 57-3. The first, manufactured by Level-1 (Rockland, MA, USA) uses a counter-current heat exchanger to warm fluid administered under pressure from bags. The second device, formerly manufactured by Haemonetics (Braintree, MA, USA), is no longer commercially available but is still in common use. The final device is manufactured by Belmont Instrument Corp. (Billerica, MA, USA) and is called the Belmont Fluid Management System (FMS). The pumped devices are pressure limited at 300 mm Hg; that is, their maximum flow rates in actual clinical use are limited by the resistance characteristics of the infusion catheter or by the maximum rate of the pump if the back-pressure is less than 300 mm Hg when maximum pump flow is attained. Of the 3 devices listed in Table 57-3, the RIS most closely approaches the characteristics of the ideal transfusion device. It has a debris filter/air removal system downstream of the warmer and pump but proximal to the final air detector, thus providing maximal embolism exclusion. The RIS also has the highest flow rate, delivering 1500 mL/min, or roughly one-third of the normal adult cardiac output, exceeding the flow capacities of all but the largest catheters. However, the RIS disposable insert is bifurcated, allowing the pumped flow to be sent to 2 infusion catheters in parallel, increasing maximum flow and volume delivered as compared to a single set due to a decrease in resistance.

Of the 2 available devices, the FMS is preferable in that it satisfies more of the requirements listed above. Its maximum flow rate does not exceed the capacity of a RIC or a percutaneous introducer sheath, but it does exceed the capacity of a 14-gauge peripheral IV or the auxiliary lumen of a centrally inserted device such as the MAC (Multi-Access Catheter, Arrow International, Reading, PA, USA) or AVA (Advanced Vascular Access, Edwards Lifesciences, Irvine, CA, USA).

The Preanhepatic Phase

As in a hepatic resection, clamping the portal triad reduces venous return. In the hepatic resection, as mentioned above, cardiac output and blood pressure do not necessarily fall. Liver transplantation almost always requires a vena cava cross-clamp, creating total vascular exclusion physiology for at least a brief duration. In contrast to portal triad clamping, total vascular exclusion of the liver via a vena cava cross-clamp reduces systemic blood pressure and cardiac output because the loss of venous return is quite large. The vena cava cross-clamp may be applied briefly to facilitate completion of the hepatectomy or for a longer time to allow construction of the hepatic venous anastomoses. Severe cardiovascular compromise during the vena cava cross-clamp may necessitate institution of venovenous bypass. Prior to committing to vena caval and portal resection, the surgeon will often "test clamp" the cava and portal vein to ensure that the patient will tolerate hepatectomy without venovenous bypass. However, more moderate decreases in cardiac output and blood pressure can be treated by vasopressor administration coupled with judicious intravascular volume expansion. Modest doses of a vasopressor during caval cross-clamp to construct caval anastomoses are apparently well tolerated, with graft and patient survival rates comparable with those obtained when venovenous bypass is used.200

Low central venous pressure does not seem advantageous during liver transplantation, in contrast to hepatic resection. For patients undergoing orthotopic liver transplantation, keeping central venous pressure less than 5 mm Hg may be associated with higher incidences of postoperative renal failure and 30-day mortality relative to patients whose central venous pressure was allowed to run between 7 and 10 mm Hg, although more recent studies indicate that it may in fact be beneficial in that it decreases intraoperative blood loss, protects graft function, and has no detrimental effects on renal function in patients undergoing OLT.201,202

As in partial hepatectomy, 2 major contributors to hemodynamic changes during liver transplantation are changes in cardiac performance due to episodic alterations in venous return (discussed above) and hemorrhage. However, these factors are only 2 of the many sources of cardiovascular instability during liver transplantation. Sepsis, acidemia, hypocalcemia due to citrate toxicity, embolism, and acute right ventricular failure are all major contributions to hemodynamic problems. The period of graft reperfusion (described below) is particularly unstable in many instances.

The goals of hemodynamic management are to provide sufficient circulating volume, vascular resistance, and cardiac output to perfuse the vital organs. This is not guided by any single parameter but rather by a synthesis of all available data, including urine output, central venous pressure (in relation to the preoperative central venous pressure and with a full appreciation of the factors that may artificially alter it), and the absence of a vasopressor requirement except during periods of inadequate venous return.

Choice of Vasopressor

With adequate volume management, vasopressors are rarely required intraoperatively except during periods of inadequate venous return (ie, during inferior vena cava cross-clamping) and transiently at liver reperfusion. Patients with higher MELD scores (>30) are more likely than those with lower MELD scores to require vasopressors.203 Administration of vasopressors is a choice between the global detrimental effects of untreated significant hypotension and the potential negative effect of vasoconstrictors on perfusion of the new graft. In animal models, both epinephrine and norepinephrine reduced graft macro- and microperfusion,204 but the functional consequences of these effects on human allograft performance or survival are unclear.

Vasopressin is a tempting choice because it is effective regardless of the pH, it reduces norepinephrine requirements, and it is effective for managing hepatorenal syndrome before transplantation. Most studies of vasopressin to date are in patients with septic or postcardiotomy shock. Vasopressin is effective in these circumstances, reducing the requirement for catecholamine vasopressor support. Limited observational studies indicate that although vasopressin raises the blood pressure, it does not compromise the microvascular circulation.205 In 1 study retrospectively reviewing the use of vasopressin in septic shock, vasopressin was associated with increased liver enzyme levels, bilirubin, or both.206 However, a recent study utilizing vasopressin in 16 patients undergoing liver transplantation showed that an infusion of vasopressin started after hepatic artery clamping and before caval clamping yielded a significant decrease in both portal vein pressure and blood flow but without a concomitant decrease in either cardiac output or intestinal perfusion.207

Terlipressin, a vasopressin analogue available in Europe and Asia, has been used in patients with cirrhosis and portal hypertension, demonstrating decreases in both hepatic and renal arterial resistance and portal venous blood flow, but without changes in portal vascular resistance.208

Adjuvant drugs, such as aprotinin, reduce the requirement for vasopressors, presumably by improving clotting performance and minimizing blood loss.209 However, these advantages must be balanced against the other potential risks of aprotinin infusion (see below).

Transfusion and Other Therapies to Maintain Intravascular Volume

The goal of volume management and transfusion in liver transplantation is to maintain sufficient intravascular volume to support a well-functioning circulation. Additionally, in many instances, the hemorrhage is sufficiently large that the anesthesiologist must intervene directly to control the composition of the circulating intravascular volume. Thus, in addition to red cell mass and intravascular volume, the anesthesiologist attends to plasma oncotic pressure, electrolyte composition, serum glucose, clotting factor levels, platelets, etc. In many cases, maintaining intravascular volume and management of coagulopathy are intertwined, so these topics are treated together in this section. Figure 57-14 gives a high-level overview of a strategy for volume and transfusion management as a function of blood loss during transplantation.

Plasma oncotic pressure is a function of the osmotically active species in the plasma (proteins and, to a very small degree, cells). Albumin and other plasma proteins, mostly synthesized by the liver, provide plasma oncotic pressure. During liver transplantation, colloids should be used to replace intravascular volume lost through hemorrhage, with the addition of formed blood components as needed to meet specific needs (eg, red blood cells for oxygen-carrying capacity).

One attractive approach to manage plasma oncotic pressure is to use fresh frozen plasma as a volume expander. This is particularly appropriate when the patient is coagulopathic due to hepatic synthetic failure, as fresh frozen plasma contains most of the proteins found in normal plasma. However, fresh frozen plasma also contains most of the citrate added to blood at the time of collection to prevent clotting. Thus rapid infusions (ie, >1 mL/kg/min) of fresh frozen plasma can chelate Ca+2, causing acute hypocalcemia with consequent vasodilation and hypotension at inopportune times.210 Figure 57-15 illustrates the consequences of rapid infusion of citrated blood products during liver transplantation.

Fresh frozen plasma is a poor choice for volume expansion when the patient is not coagulopathic, as each unit of fresh frozen plasma carries with it the potential to trigger transfusion-related lung injury. Also, liver transplantation entails the construction of multiple low pressure, low flow anastomoses. Some practitioners believe that maintaining a slightly hypocoagulable state lessens the possibility of unwanted hepatic or portal venous thromboses. Thus, in the absence of significant coagulopathy, 5% albumin solution is probably a better choice for volume expansion. Synthetic colloids comprised of long-chain polysaccharides are available but are not popular because they can interfere with clot formation. Additionally, anesthesiologists must be cognizant of not volume overloading the patient, as excessive volume postreperfusion can add to liver congestion and swelling within the capsule, likely amplifying ischemic reperfusion injury.

Transfusion and Other Therapies to Maintain Coagulation Capacity

Coagulation is monitored using standard laboratory tests, augmented in some cases by point-of-care functional tests, and ultimately by clinical correlation of the laboratory test results with direct observation of the surgical field. The basic tests to monitor coagulation status are the prothrombin time, the activated partial thromboplastin time, and the platelet count. D-dimer and fibrinogen levels provide information about the presence of clot lysis, and the latter, the ability to form clot. However, these tests provide a far-from-complete picture of a patient's coagulation performance. Many centers use thromboelastography to obtain near-patient diagnostics of clot initiation, formation, and lysis.211,212 Thromboelastography is a mechanical test described in detail in Chapter 15. The test is sensitive to extraneous influences (including environmental disruption), and it is not well standardized. However, thromboelastography is useful in liver transplantation because, unlike other tests, it gives information about clot lysis.212

Coagulation performance during liver transplantation in the patient with end-stage liver disease tends to follow a predictable course.213 Patients with hepatic synthetic failure start out hypocoagulable, and with appropriate transfusion of fresh frozen plasma as part of the volume replacement strategy, coagulation status tends not to get significantly worse during the preanhepatic and anhepatic phases of the operation. After reperfusion of the graft, a clot lysis syndrome develops, and some patients become hypercoagulable at the same time (ie, disseminated intravascular coagulation develops).213 Even patients who present with normal hepatic synthetic function and no coagulopathy can develop a dilutional coagulopathy as well as the reperfusion clot lysis syndrome. A worsening coagulopathy postreperfusion despite adequate replacement of coagulation factors, platelets, and fibrinogen may herald a nonviable graft and the immediate need for a replacement organ.

Volume replacement therapy should attend to preserving or moving clotting potential toward a normal state as part of the effort to reduce blood loss. However, transfusion therapy and coagulation management are no substitute for good surgical technique. Successful transplantation requires attention to both. Typically, fresh frozen plasma is used to replace clotting factors. Liver transplant patients are frequently in a state of low-grade disseminated intravascular coagulation and thus consume fibrinogen and clotting factors even in the absence of massive hemorrhage. Fresh frozen plasma usually supplies sufficient fibrinogen, but cryoprecipitate may be helpful if the fibrinogen levels become unacceptably low.

Platelets are rarely needed prior to graft reperfusion, even in patien ts with low platelet counts (eg, 50000/ml). Furthermore, many patients manifest splenic sequestration of platelets and have no response to transfusion, both exposing the patient to unnecessary risk of transfusion and wasting a valuable blood component.

Antifibrinolytic drugs and other procoagulants can be used prophylactically in the preanhepatic phase to minimize bleeding. These drugs are discussed in detail in the section on the postanhepatic phase of liver transplantation.

Anhepatic Phase

The anhepatic phase of liver transplantation is frequently described as the time from explantation of the diseased liver to the reperfusion of the new liver. However, the anhepatic phase of the operation actually begins once the native liver is sufficiently compromised to have no further function. During liver transplantation, this is usually when the hepatic artery is clamped, which can precede portal and hepatic vein clamping by many minutes. During this time, especially in the setting of portal hypertension, the diseased liver receives no oxygenated inflow and begins to die, with a consequent effect on the patient's acid–base status. However, once the liver is completely excluded from the circulation, this problem ends. After this, the anhepatic phase is often a relatively quiet period in the case. Bleeding should be under control, and the surgeons are engaged in the delicate task of constructing the venous anastomoses. During the construction of the venous anastomoses, the liver is kept on ice (Fig. 57-16, left panel).

Any drugs dependent on hepatic metabolism begin to accumulate once the portal vein and hepatic artery are clamped. Thus infusions of drugs should be titrated to effect. Of course, drugs not dependent on hepatic metabolism (eg, inhaled agents, remifentanyl) are unaffected by this transition.

The anesthesia team should attend to immunosuppression during the early anhepatic phase. The patient will have received an induction dose of an immunosuppressant, such as mycophenylate mofetil, prior to coming to the operating room. Obviously, this should be confirmed prior to starting the case. Typically, a modest dose of steroid (eg, 100-500 mg methylprednisolone) is given in the operating room as the new liver is initially placed into the recipient (before opening of the anastomoses; Fig. 57-16, right panel). For patients with hepatitis C, alternative regimens may be used such as an infusion of rabbit antithymocyte globulin begun at the completion of the hepatectomy and 10 mg methylprednisolone when the liver is placed into the recipient. In practice, the immunosuppression regimen is chosen by the surgeon, and the anesthesia team should ascertain the drugs, doses, routes, and timing prior to starting surgery.

Hemodynamics frequently stabilize during the anhepatic phase, particularly if a piggyback technique is used. This period of stability may derive from the fact that the rapid alterations in venous return during gross manipulations of the liver are superceded by more delicate tasks. If an en-bloc resection has been used with a complete vena cava cross-clamp, the circulation may still be stable if venovenous bypass is also used. However, if the vena cava is clamped without a venous return conduit, it is often necessary to support the circulation with a potent vasoconstrictor, preferably an agent with some inotropic activity such as norepinephrine.

Hypotension with diminished central venous pressure may occur even with significant preservation of venous return during the anhepatic phase. Lower extremity and splanchnic congestion lowers the effective circulating volume and central venous pressure above the diaphragm, with attendant hypotension. However, it is important not to overtreat this condition with aggressive volume replacement, as it can lead to hypervolemia at the time of graft reperfusion. Instead, it is preferable to support the circulation with a low dose of a vasopressor, anticipating the mobilization of blood from below the diaphragm once the liver is reperfused.

Finally, some poorly understood physiologic feature of the anhepatic phase might directly affect left ventricular performance, contributing to hypotension. Echocardiographic studies of ventricular function demonstrate, for example, that left ventricular shortening fraction diminishes during the anhepatic phase, relative to the preanhepatic phase, then returns to normal214 after reperfusion. Although this was a small study, a more recent and larger study revealed a decrease in right ventricular ejection fraction from baseline during the anhepatic phase of liver transplantation in 20 patients, but with a gradual return to baseline 30 minutes postreperfusion.215

Electrolyte Management

Serum electrolytes and acid–base balance are subject to wide and rapid swings during liver transplantation, especially if the case is bloody and extensive transfusion is required. These are most severe during the anhepatic phase, when even the small residual function of the native liver has been removed. However, even during the preanhepatic phase, the patient's acid–base, electrolyte, red cell mass, and coagulation statuses are likely to change rapidly due to brisk hemorrhage, various cross-clamping maneuvers, and compression of abdominal vasculature, as well as potentially massive transfusion. Thus frequent monitoring of arterial blood gases, serum electrolytes, red cell mass, and laboratory measures of clotting is mandatory from the beginning of surgery.216 During the active portion of the case, we interpret and respond to laboratory results as they are returned, allow for equilibration, and then recheck the laboratory values.

Metabolic acidosis may develop in the anhepatic phase due to portal cross-clamping, as well as partial or complete inferior vena cava (IVC) cross-clamping, creating imperfect lower extremity and splanchnic venous return. There is also loss of any residual ability to clear organic acids. At the time of reperfusion, the donor liver and underperfused tissues from the patient release acid loads. Ongoing transfusion of low-pH, citrated blood products also contributes to the acidemia.

Various maneuvers can mitigate acidemia during liver transplantation. Hyperventilation can be used to establish an acute respiratory compensation for metabolic acidosis. Sodium bicarbonate can be administered to correct acidemia, although the need to minimize sodium loads, particularly in patients who are hyponatremic, may limit the usefulness of bicarbonate. Sodium bicarbonate must not be coadministered in the same infusion as Ca+2 solutions, as the combination will precipitate. Tromethamine (THAM) can also be used to control acidemia.

Acidemia at the time of reperfusion should be corrected by hyperventilation and administration of bicarbonate. This minimizes the hemodynamic and cardiac effect of the acid load and metabolic waste products released by reperfusion of the allograft. However, overzealous correction of metabolic acidemia is undesirable, particularly in the setting of massive transfusion. This is because the new liver clears citrate and organic acids, resulting in a rebound metabolic alkalosis; this may be seen developing even during the late neohepatic phase. Thus a reasonable strategy is to use modest hyperventilation to keep the pH near normal, with the use of bicarbonate of THAM only as needed to keep the pH above approximately 7.35 after respiratory maneuvers have been fully implemented.

Patients presenting for liver transplantation may be either hyper- or hypokalemic, depending on whether potassium-sparing or potassium-wasting diuretics have been used to control ascites. Potassium balance is also influenced by the underlying renal function or compromise. Serum potassium is subject to strong influences favoring hyperkalemia during the anhepatic phase. This may lead to large swings in serum potassium, especially if renal function is compromised or if large volumes of blood products are required. Additionally, splanchnic ischemia during the case tends to elevate serum potassium. Metabolic acidosis tends to worsen hyperkalemia. Finally, the preservative solution in the donor liver is rich in potassium.

Dangerous levels of serum potassium should be treated to avoid myocardial irritability and cardiac dysrhythmias. In patients with preserved renal function, this is accomplished initially by controlling the pH, by the use of potassium-wasting diuretics if the volume status permits, and by avoidance of potassium-containing solutions. Bicarbonate to increase pH tends to drive potassium intracellularly, whereas Ca+2 administration to replete deficits stabilizes irritable myocardium. Rapid or persistent increases in serum potassium are treated with glucose and insulin to drive potassium intracellularly by glucose cotransport. The combination of insulin and glucose predictably reduces serum potassium even during the anhepatic phase.217

Inhaled β2-agonists, including albuterol and levalbuterol, may be used to lower serum potassium by driving serum potassium intracellularly, and recently salbutamol was used to treat hyperkalemia resistant to other treatments during the anhepatic stage of a patient undergoing liver transplantation.218

If renal function is severely compromised, renal replacement therapy, either by continuous venovenous hemofiltration or by conventional dialysis, may be warranted to control serum potassium, sodium, and pH. Intraoperative renal replacement therapy can strain the resources of hospital dialysis services, so early consultation with a dialysis nephrologist is important once it appears that such therapy is needed.

Calcium is required for smooth muscle and myocardial contractility. Thus hypocalcemia during liver transplantation depresses inotropy (manifested as depressed cardiac index, reduced cardiac stroke index, and left ventricular work index219) and reduces vascular tone. In this setting, vasopressor activity is also compromised. Hypocalcemia may also interfere with clotting, as calcium is a required cofactor for many clotting factors. Thus it is important to monitor and correct abnormal serum calcium. During liver transplantation, serum ionized calcium tends to decrease due to vigorous administration of citrated blood products. As a rule of thumb, administration of 6 units or more of acid citrate dextrose (ACD)-preserved packed red blood cells requires supplementation of calcium.

Calcium can be repleted with calcium gluconate or calcium chloride. The positive inotropic effects of calcium administration are quick in onset but short lived. Again, overaggressive correction of ionized calcium intraoperatively precipitates a rebound hypercalcemia during the postoperative period as the liver metabolizes the citrate chelator. Thus the goal for intraoperative calcium management is to achieve the lowest ionized calcium concentration consistent with good cardiac performance and coagulation, typically 0.9 to 1.0 mmol/L. Postoperative hypercalcemia is treated with hydration and furosemide diuresis.

Serum sodium is frequently low in liver transplant patients due to the formation of ascites, the effects of renal failure, the use of diuretics, or combinations of all of these. It is important to avoid accidental aggressive overcorrection of hyponatremia, as too-rapid correction of hyponatremia can cause central pontine myelinolysis, an irreversible neurologic injury. Unfortunately, many useful replacement fluids contain sodium. For example, fresh frozen plasma, packed red blood cells, and 5% albumin all contain sodium at normal physiologic concentrations. To maintain intravascular volume while avoiding too-rapid correction of hyponatremia, a strategy of administering colloids along with 5% dextrose while inducing a diuresis of sodium and water with furosemide may be used. In patients with renal failure, dialysis or continuous venovenous hemofiltration against a low sodium bath can be used to remove the volume without increasing sodium too abruptly.

Glucose management during liver transplantation is usually fairly straightforward despite the liver's central role in glucose handling. The liver is the major site for gluconeogenesis, and this function is preserved to some degree in even the most severe cases of end-stage liver disease. Thus complete hepatectomy creates the possibility of intraoperative hypoglycemia during liver transplantation. This is particularly true if the anhepatic phase of the operation is prolonged.

Serum glucose during liver transplantation is also influenced by exogenous sources, including carrier infusions and the release of glucose from graft preservation solution. Thus intraoperative hypoglycemia is rarely a problem in practice, especially if some IV fluids (eg, drug-carrier infusions) contain 5% dextrose. Additionally, the use of methylprednisolone during the anhepatic stage often results in serum hyperglycemia. The liver is at once the major site of gluconeogenesis and insulin-mediated glucose uptake. Therefore, the anhepatic phase may be marked by hyper- or hypoglycemia, both of which should be avoided and treated. As in the case of other major surgeries, tight glycemic control is probably beneficial, and blood glucose should be measured frequently. Target blood glucose should be 150 to 200 mg/dL.

Renal Protection during Transplantation

Renal failure requiring renal replacement therapy (eg, dialysis or continuous venovenous hemofiltration) is common after liver transplantation, with rates of approximately 5% to 10%.220,221 Peritransplantation acute renal failure requiring renal replacement therapy is associated with higher mortality as compared with liver transplant patients not requiring dialysis.222 It is not clear whether there is a cause-and-effect relationship between acute renal failure and death after liver transplantation, but renal failure is an unwelcome outcome.

Protection of renal function probably depends, among other things, on maintaining renal perfusion during the liver transplant procedure. Renal perfusion is subject to many insults during transplantation, including hypovolemia and increased resistance to venous outflow due to vena cava compression or cross-clamping. Maintaining an adequate circulating volume facilitates preserving renal function. However, this is at times difficult, and a selective medical therapy to protect the kidney in the peritransplant period would be useful.

Attention has focused on selective splanchnic vasodilators, such as low-dose dopamine or, more recently, fenoldopam, as protective agents during major surgery. Fenoldopam has recently been studied in liver transplant patients randomized to 1 of 3 groups (fenoldopam, low-dose dopamine, or placebo) prior to surgery. Neither fenoldopam nor dopamine was superior to placebo for preservation of any measure of renal function (urine output, serum creatinine, creatinine clearance, use of diuretics, or use of pressors) immediately after surgery. On the third and fourth day after transplantation, creatinine clearance was reduced in patients receiving placebo or low-dose dopamine, whereas it was preserved in patients receiving fenoldopam.223 The authors concluded that fenoldopam might counteract the renal arterial constrictive effects of cyclosporine.223

In this small, unblinded study, neither low-dose dopamine nor fenoldopam demonstrated obvious renal protective effects in the early perioperative period.223 Similarly, another small study by the same researchers demonstrated that fenoldopam led to better creatinine and blood urea nitrogen values at day 3 after liver transplant, but the functional effect of this result on the incidence of acute renal failure was not demonstrated.224 Slightly lower (but not statistically significant) BUN and creatinine levels were observed in OLT patients who received continuous infusions of fenoldopam, although increased splanchnic perfusion was seen in the study group as compared to placebo.225

More conventional approaches to renal protection include maintaining adequate circulating volume and perfusion pressure. Urine output is commonly used to judge real function in the operating room, and "target" urine flows of 1 mL/kg−1/h−1 are frequently sought. When the urine output falls below this target and the circulating volume and perfusion pressure are judged to be adequate, furosemide or mannitol are sometimes used to increase the urine output.

Reperfusion of the Graft

Preparation for reperfusion involves optimizing volume status and hemodynamic performance and preparing the operating room for a potentially chaotic reperfusion period. Potential distractions related to the anesthetic (eg, the need to redose drugs, change syringes, carrier infusions) should be addressed in advance. Laboratory studies should have been sent in time for the results to arrive 5 minutes prior to reperfusion. Constant communication between surgeon and anesthesiologist must be the rule rather than the exception, with each team informing the other well in advance of any major intervention or treatment.

Abnormalities in pH, serum potassium, or calcium should be corrected prior to reperfusion. Sodium bicarbonate, glucose and insulin, and calcium chloride should be prepared and ready for use. Some practitioners use combinations of these agents prophylactically prior to reperfusion.174

Vasopressors may be required at the time of reperfusion and should be available for immediate infusion. Among the commonly used vasopressors, there is no compelling or logical best choice, so institutional preferences prevail. Epinephrine, dopamine, and norepinephrine are all acceptable choices, although some practitioners may consider the use of phenylephrine or vasopressin. Vasopressors are also commonly used prophylactically at reperfusion, frequently as a small bolus such as epinephrine, 10 mcg.

Just prior to reperfusion, the new liver is flushed antegrade from the portal vein to the hepatic vein to wash out the preservative solution (which contains large doses of potassium and heparin). Flushing is accomplished with crystalloid, colloid (such as 5% albumin), or blood. A blood flush is performed by constructing the portal and hepatic venous anastomoses, after which the portal anastomosis is closed but the hepatic venous anastomosis is left open. The portal vein cross-clamp is removed, and blood is allowed to flush the liver and run out into the field where it is recovered by suction. Concomitant with this controlled hemorrhage, fluid should be rapidly transfused to maintain euvolemia.

Graft reperfusion has its most obvious effect on cardiac performance, and the anesthesia team should be prepared for pulmonary hypertension and acute right heart dysfunction. Liver transplantation in and of itself does not appear to cause right heart dysfunction.226 However, release of preservative solution, air, clot, and debris (as well as acidemic blood from the reperfused splanchnic circulation) into the pulmonary vasculature can cause sudden and severe pulmonary hypertension, elevated right heart pressures, and right ventricular failure (as mentioned previously). Systemic pressure (and coronary perfusion pressure) decreases due to inadequate left ventricular preload. The elevated right heart pressures may open an occult patent foramen ovale, with risk of paradoxical embolism.227 The central venous pressure frequently increases due to right heart and pulmonary congestion. Ordinarily this is desirable to a point to ensure right ventricular preload. However, in the immediate reperfusion period, elevated central venous pressure compromises graft perfusion and may contribute to early graft failure. Thus it becomes important to preserve or reestablish efficient right ventricular pumping and a low-resistance pulmonary circulation.

Pulmonary hypertension, right ventricular overload, and the resulting central venous congestion reduce the hepatic perfusion pressure, which is simply the difference between the portal and central venous pressure when only the venous anastomoses have been constructed. The portal venous pressure is not typically measured, so the hepatic perfusion pressure is not directly accessible. However, inadequate perfusion pressure can be deduced if the liver becomes engorged. This alarming appearance somewhat mimics that of hyperacute rejection. To avoid confusion, the hepatic perfusion pressure is ideally controlled by keeping the central venous pressure low at the time of reperfusion. This is not possible in the event of acute pulmonary hypertension unless inotropes and selective pulmonary vasodilators are used. Typically, the heart is supported with an inotrope, and the lungs are hyperventilated to raise the pH and induce vasodilation. Inhaled nitric oxide and/or a low-dose infusion of nitroglycerine may be useful at this point.

As stated previously, good communication between the surgical and anesthesia teams is also important to minimize the effect of reperfusion. Reperfusion should not occur until the anesthesia team has optimized the patient's physiology, and this should be accomplished in time to allow prompt reperfusion. In the event of severe problems at reperfusion, the surgeon can partially reclamp the portal vein to lessen the effect of the effluent from the new liver.

The combined effect of multiple insults on cardiac and pulmonary performance at reperfusion may lead to cardiovascular collapse. Advanced cardiac life support protocols directed at the presumptive major problem should be promptly initiated while the underlying insults are identified and corrected. In the event of cardiopulmonary arrest not responsive to pharmacologic support (or due to reversible causes such as pulmonary embolus), mechanical circulation and oxygenation can be provided by percutaneous femoral venoarterial cardiopulmonary bypass with acceptable survival.228

In the early postreperfusion period, severe volume overload from overaggressive fluid replacement during the period of poor venous return may compromise hepatic perfusion even with adequate cardiac performance. If the problem is slight, then it may be possible to administer furosemide to induce diuresis, or to wait for the blood volume to fall due to bleeding. In the case of severe volume overload and poor graft perfusion, phlebotomy from a large port on a central venous catheter is a logical option.

Neohepatic Phase

The neohepatic phase begins with the initial reperfusion of the liver. Frequently, the next step is to construct the hepatic arterial anastomosis. The liver ultimately needs a high-pressure, oxygenated perfusion source, and the surgical team will turn its attention to this as soon as the immediate effects of venous reperfusion have passed. Opening of the hepatic arterial anastomosis usually has little or no hemodynamic effect.

An acute clot lysis syndrome frequently develops in the early neohepatic phase. This manifests clinically as diffuse bleeding from previously coagulated sites in the surgical field, new oozing from previously quiescent vascular catheter insertion sites, and ongoing transfusion requirements. Laboratory analysis shows a further elevation of the prothrombin time relative to baseline, and a sometimes profound elevation of the partial thromboplastin time (eg, to >150 seconds), as if the patient had received a large dose of heparin. Thromboelastography demonstrates poor clot initiation and rapid dissolution of clot. Figure 57-17 shows sequential thromboelastograms obtained from a single patient during the course of transplantation.229

The cause of this clot lysis syndrome is not completely understood, which limits the ability to tailor treatment to specific causes. Multiple mechanisms have been proposed and may operate simultaneously, including release of heparin (from preservative solution) during reperfusion or release of endogenous activators of tissue plasminogen activator and/or endogenous heparinoids from the graft.213

A central goal in this phase of the transplant is to stop clot lysis. A key first step toward achieving this goal is to provide adequate levels of platelets and factors to support clotting in the face of ongoing consumption, with the expectation that a functioning graft will begin to provide appropriate clot lysis inhibitors and clotting factors on its own. One could consider administering a small (20-50 mg) dose of protamine213 in the event that clot formation is suspected to be deficient, especially if the liver flush prior to reperfusion was not optimal and the patient might have received heparin from the graft.

Fibrinolytic activity is frequently increased during liver transplantation, reflecting reduced hepatic clearance of tissue plasminogen activating factor (tPA) during the anhepatic phase and release of tissue plasminogen activator from the epithelial cells of the reperfused graft.230-232 In addition, plasminogen activator inhibitor-1 activity is reduced231 during transplantation. Fibrinolysis probably contributes to the unwanted clot lysis syndrome after reperfusion.

Strategies for reducing fibrinolysis and transfusion requirements include the use of antifibrinolytic agents such as aprotinin,233 tranexamic acid, and ϵ-aminocaproic acid.234 However, the use of antifibrinolytics in liver transplantation is somewhat controversial because of concerns about unwanted thrombosis.

ϵ-Aminocaproic acid and tranexamic acid are both synthetic analogues of the amino acid lysine. ϵ-Aminocaproic acid and tranexamic acid competitively inhibit the binding of plasminogen (a lysine protease) to lysine residues on fibrin, thus inhibiting fibrinolysis. Both drugs also prevent the conversion of plasminogen to plasmin, again by virtue of acting as competitive antagonists of a lysine protease. ϵ-Aminocaproic acid is used during liver transplantation as a loading dose (typically a 1- to 2-g bolus over 1-10 minutes), followed by infusions of 1 to 2 g per hour. It reliably arrests fibrinolysis as assessed by thromboelastography (see Fig. 57-17).229 The drug is eliminated by the kidney, with 65% of a dose appearing unchanged in the urine. The elimination half-life of ϵ-Aminocaproic acid is about 2 hours.

Tranexamic acid is 6 to 10 times more potent than ϵ-aminocaproic acid and has a longer elimination half-life. It is also renally eliminated, with 95% of the drug appearing unchanged in the urine. It is the least well studied of the 3 major antifibrinolytics.234 Dose rates between 2 mg/kg/h and 40 mg/kg/h have been reported in small studies with either ϵ-aminocaproic acid or aprotinin as comparisons.

Aprotinin is a protease inhibitor isolated from the lungs of swine or cows. It inhibits a variety of human proteases, including plasmin, trypsin, kallikrein, chymotrypsin, activated protein C, and thrombin. These proteases are important in fibrinolysis and coagulation, as well as complement activation and inflammation. Each uses a serine residue for catalysis at the active site, and aprotinin acts by forming a specific aprotinin-active site serine complex with each protease. Aprotinin has an approximately 1-hour redistribution half-life after a bolus, and a 7- to 10-hour elimination half-life. It is given as a bolus, followed by an infusion. A typical bolus is 2 million kallikrein inactivator units (KIU), followed by an infusion of 500000 to 1 million KIU per hour.234

The use of antifibrinolytic drugs may have deleterious effects. There is anecdotal evidence that antifibrinolytic therapy may increase the incidence of thrombotic events during liver transplantation, including fatal pulmonary thromboembolism.235 Additionally, as mentioned previously, aprotinin is no more effective than the lysine analogues, but it is associated with excess morbidity and mortality relative to these other drugs when used in cardiac surgery.132 This suggests that during liver transplantation, antifibrinolytic agents should be reserved for patients who have a relatively high risk of severe hemorrhage,236 and aprotinin might best be avoided altogether. However, the clotting cascade in liver transplant patients is quite deranged, and cardiopulmonary thromboembolism, even in the absence of exogenous procoagulants, may be more common than is usually appreciated.169

Thus antifibrinolytics might be considered for rescue if bleeding becomes a problem in the postanhepatic phase,234 as judged by the disappearance of clot from the surgical field, or as a prophylactic measure in patients expected to have severe bleeding problems (eg, multiorgan transplant in a patient with renal failure). Balanced against this cautious approach are some practices that advocate the use of antifibrinolytics prophylactically, in advance of any pathologic bleeding.234 However, in addition to enhanced fibrinolysis, many other factors contribute to blood loss late in orthotopic liver transplantation, including coagulopathy due to synthetic failure, thrombocytopenia, platelet dysfunction, dysfibrinogenemia, dilutional coagulopathy, hypothermia, and bleeding from surgical technical problems. As postreperfusion fibrinolysis is largely a diagnosis of exclusion, all of these other factors must be ruled out before administration of potent procoagulants.

Procoagulant agents, such as purified specific clotting factors, can also be used, either prophylactically or as an attempted therapy for excessive bleeding. For example, in 1 study, recombinant factor 7 corrected coagulopathy when given as single bolus prior to transplant, but there was no effect on transfusion requirements.237 In a different study, recombinant factor VII was used in a small number of patients without clear evidence of clinical harm or benefit.238 Recombinant factor VII has the theoretical advantage of being selective only for areas that are bleeding—that is, those areas that have sustained tissue damage. This is because recombinant factor VII requires tissue factor for full activity, and tissue factor is only available in areas in which the subendothelial layers are exposed. Of course, the vascular anastomoses in the new graft would have exposed tissue factor, at least theoretically increasing the risk of thromboses of the anastomoses. Furthermore, recombinant factor VII is apparently not as selective as initially hoped. A recent report documents many episodes of arterial and venous thromboses distant from the hoped-for site of action (eg, cerebrovascular accident, myocardial infarction, pulmonary embolism, and deep venous thrombosis) when recombinant factor VII was used in various "off-label" applications.134

If the fibrinolysis reaction cannot be controlled, the patient will have an ongoing transfusion requirement. The anesthesia team should quantify the hourly transfusion needs in the neohepatic phase and make preparations to meet this during the end of the case, the move from OR table to ICU bed, transport to the ICU, and in the intensive care unit itself.

L-arginine, an essential component of the L-arginine/nitric oxide (NO) synthase pathway, is diminished in patients postreperfusion due to liberation of arginase from the donor graft, and may lead to hemodynamic changes in the reperfusion stage.239,240 With a decrease in L-arginine and an increase in arginase, there is a concomitant increase in L-ornithine levels.241 Blockade of the L-arginine/NO synthase pathway is implicated in hepatic apoptosis and liver transplant preservation injury, and blockade of arginase or administration of L-arginine protects against hepatic warm ischemia reperfusion injury and has demonstrated improvements in cardiac output and liver blood flow, while reducing pulmonary vascular resistance.242-244

During the neohepatic phase, the anesthesia team prepares for the postoperative disposition of the patient. Most liver transplant recipients are discharged from the operating room to an ICU bed. The anesthesia team seeks to manage this transition as smoothly as possible. The patient should be transported on an ICU bed, with all necessary infusions running and the patient fully monitored. Comprehensive communication between the operating room and the ICU team is essential to facilitate the smooth transition of care.

The anesthesia team also prepares for the early postoperative care of the patient. One large, multicenter study looking at early extubation in 391 patients demonstrated that early extubation is safe under specific conditions, with only 7.7% having adverse outcomes secondary to either pulmonary issues or need for additional surgery.245 Suitability for extubation is influenced by many factors. Among these are the intraoperative transfusion requirement (as a warning of possible airway edema); the presence or development of pulmonary, cardiac, and renal compromise; and the presence and severity of encephalopathy.246 Fluid administration and possible volume overload are some of the many factors that can interfere with the patient's readiness for extubation at end of case. Controlled fluid administration supported by adjuvant vasopressors led to reduced rates of reintubation in 1 study.247 Intraabdominal hypertension is common after orthotopic liver transplantation and limits the potential for extubation. Intraabdominal hypertension (pressure >25 mm Hg in the bladder) developed in 32% of patients248 in 1 series. It is expected that these patients are less likely to meet criteria for early extubation and are harder to wean from the ventilator.

If in doubt, it is always acceptable and prudent to leave the patient intubated for pulmonary support in the early postoperative period. Postoperative mechanical ventilation allows the team to focus on ongoing transfusion requirements, to exclude the possibility of intra-abdominal hypertension, and to gradually prepare the patient for extubation. Despite the concern about elevated intra-abdominal pressures on graft viability, postoperative application of positive end-expiratory pressure (PEEP) does not have a major effect on graft function, although in half of the patients the cardiac output declined with PEEP.249 This is encouraging because PEEP may be needed to counteract the pulmonary consequences of intra-abdominal hypertension.

Pain management is relatively straightforward after liver transplantation. Many patients remain intubated and receive potent opioids as sedatives. Epidural analgesia is traditionally avoided due to the profound coagulopathy manifested by end-stage liver disease patients, both preoperatively and in the postoperative period, although some centers report successful use of thoracic epidural anesthesia for patients who meet strict criteria.250 Furthermore, orthotopic liver transplant patients have less postoperative pain than hepatectomy patients.251 The reason for this difference in pain threshold is unclear, although some have implicated the steroids used for immunosuppression. Steroids have analgesic properties in other patient populations.252

Perioperative Complications of Liver Transplantation

Complications of liver transplantation are frequent. Here we focus on the early complications of liver transplantation—that is, those that occur in the operating room or the intensive care unit within hours or days of the procedure.

Complications of massive transfusion should be mentioned at this juncture. Risks of massive transfusion consist of pulmonary edema, transfusion-related acute lung injury (TRALI),253,254 and viral infection. Analysis of pulmonary edema from liver transplant recipients has demonstrated rich edema fluid/plasma protein levels, consistent with increased permeability pulmonary edema and TRALI.255 Increased use of blood products, and more specifically plasma and platelets, is associated with an increased incidence of TRALI in liver transplantation.256 Various strategies including volumetric diffusive respirator (VDR) ventilation, PEEP, and prone ventilation have been successfully used in the treatment of posthepatic transplantation patients with TRALI.257

Much attention has focused on the transmission of cytomegalovirus. The incidence of cytomegalovirus transmission is much higher with a cytomegalovirus-infected donor organ than with blood that has not been screened or reduced for cytomegalovirus.258 Cytomegalovirus is an independent risk factor for mortality after liver transplantation, due in part to allograft rejection or chronic graft dysfunction.259 Many centers now use routine pharmacoprophylaxis against cytomegalovirus infection, as leukoreduction of blood or the use of cytomegalovirus-negative donors has been deemed impractical by many blood banks.

Massive transfusion contributes to the development of intra-abdominal hypertension. Patients with intra-abdominal hypertension had a higher incidence of renal failure, more postoperative complications, and higher intensive care unit mortality than patients without this complication.248

Anastomotic leaks involving the vascular or bile duct connections can prompt reexploration and anastomotic revisions. Anastomotic bleeding tends to be most severe during the latter stages of the surgery and on the first postoperative day. An ongoing brisk transfusion requirement, an expanding abdomen, or falling hematocrit can prompt reexploration even before leaving the operating room. There should be a low threshold to reexplore for bleeding, as an abdomen full of blood or clot is a nidus for infection. In addition, the compressive effect of a large hematoma potentially compromises graft, pulmonary, and cardiac function. Reexploration in the early postoperative period should be handled with the same degree of preparation as the original transplant procedure. In particular, a disruption of one of the anastomoses without surgical control of the vessel can lead to massive hemorrhage.

Other vascular complications necessitating prompt reexploration include stenosis or thrombosis of the anastomoses of the liver vessels. This may occur intraoperatively or postoperatively. In the intraoperative and postoperative period, vascular patency is monitored by serial ultrasound examinations.260 Hepatic artery thrombosis is the most common vascular complication in the postoperative period.260 Radiologists must be vigilant and knowledgeable of locations of surgical anastomoses to help identify potential sites for complications in the immediate postoperative period.261 If hepatic artery thrombosis is not diagnosed and treated promptly, severe graft dysfunction or total graft loss will occur. Treatment of hepatic artery thrombosis typically requires urgent reoperation to remove the obstruction, although endovascular treatment has been successfully used.262 If flow cannot be restored, the patient probably needs to be relisted for liver transplantation as a Status I candidate. However, there is a small but growing experience of temporizing with hyperbaric oxygen therapy.263

Neurologic complications are relatively common after liver transplantation. Their causes are multifactorial, related both to intraoperative and early postoperative events, as well as the ongoing effects of toxic immunosuppressants. Of particular concern to anesthesiologists is central pontine myelinolysis,264 which has been associated with rapid correction of hyponatremia in the peritransplant period. This syndrome is characterized by a general neurologic decline hours or days after a sudden correction of hyponatremia. Much attention focuses on central pontine myelinolysis because patients presenting for liver transplantation are frequently hyponatremic and because of the association between the syndrome and an inciting event (eg, rapid correction of hyponatremia). However, central pontine myelinolysis is a relatively rare neurologic complication of liver transplantation. For example, in a study of 463 patients having transplants performed at multiple centers,265 93 (20.1%) patients had peritransplant neurologic complications. Of these, 6 patients (1.2% of the starting cohort) were confirmed to have central pontine myelinolysis. Two of these patients had rapid increases in their serum sodium for a period of hours during transplant; the rest did not.265 In another multicenter prospective cohort study involving 1730 liver transplant patients, there were 60 patients with radiologically confirmed central nervous system lesions. Of these, 5 patients (0.3% of the original cohort) had central pontine myelinolysis.266

Procedures for Portal Hypertension and Ascites

A variety of surgical and minimally invasive interventional procedures have been developed to ameliorate the problems associated with liver disease. Portal hypertension underlies most of these problems, leading to ascites or to varices that are the source of life-threatening hemorrhage. Procedures to alleviate portal hypertension and ascites are listed in Box 57-10. These are divided into nonshunting procedures (ie, those that do not seek to redirect portal venous flow) and shunting procedures. Nonshunting procedures are aimed at controlling hemorrhage from portosystemic varices. Varices at the gastroesophageal junction are the most troublesome of these, but they are amenable to endoscopic therapy. Shunting procedures redirect the portal venous flow into the systemic venous circulation via a nonvariceal conduit, thus relieving portal hypertension, decompressing varices, and at the same time relieving ascites. Because these shunts bypass the liver, they may create new problems due to encephalopathy. Shunting procedures have undergone a transformation from open surgical procedures on high-risk patients (high Child-Turcotte-Pugh scores predicting elevated perioperative morbidity and mortality) to a more minimally invasive approach.

Nonshunting Procedures for Portal Hypertension

These procedures (eg, ablation of esophageal varices or hemorrhoids) aim to reduce variceal hemorrhage. The procedures ligate decompressive alternate conduits for portal blood flow around the cirrhotic liver, so they are expected to worsen portal hypertension and ascites. Minimally invasive procedures have largely replaced surgical approaches for managing varices. Minimally invasive approaches include endoscopic ligation or embolization (eg, endoscopic sclerotherapy of esophageal varices) and percutaneous embolization procedures. Many of the minimally invasive procedures to obliterate varices are performed outside of the operating room (ie, in remote procedure areas in the hospital), frequently with local or topical anesthesia and conscious sedation provided under the direction of the proceduralist. Thus anesthesiologists now encounter relatively few patients presenting for variceal ligation, and frequently these are only the most complex procedures, the sickest patients, or both. Anesthesia for these patients should follow the model for patients with severe decompensated liver disease as outlined in Chapter 15.

Portosystemic Shunts

Portosystemic shunts aim to reduce the hydrostatic pressure in the portal venous system by providing an alternate, nonvariceal conduit that bypasses the cirrhotic liver. A variety of approaches have been developed to shunt portal venous blood away from the liver and into the central venous circulation, first by open surgical procedures and now increasingly via percutaneous approaches. Again, there is a group of patients whose medical conditions or procedural needs preclude a minimally invasive approach, so a limited population of patients present for surgical portosystemic shunts.

Open Portosystemic Shunts

Surgical or "open" portosystemic shunts are listed in Box 57-10. Each is designed to reduce portal hypertension, differing mostly in the topology of the vascular connection that is constructed. The surgery is in every case an open abdominal procedure in which venous vascular anastomoses are constructed. Anesthesia for open portosystemic shunts should follow the model described for patients with decompensated end-stage liver disease as described in Chapter 15.

Transjugular Intrahepatic Portosystemic Stent Shunts

Transjugular intrahepatic portosystemic stent shunts (TIPSS) are indicated for patients with refractory ascites due to portal hypertension. Refractory ascites carries substantial morbidity (ie, spontaneous bacterial peritonitis, renal failure) and has a 1-year survival of less than 50%. Thus removal of ascites may benefit these patients, and TIPSS is successful in decompressing the portal system in about 90% of cases. Two meta-analyses of studies comparing TIPSS with conventional therapy (periodic large-volume paracentesis) indicates that TIPSS is superior for removing ascites but at the expense of a higher incidence of hepatic encephalopathy.267,268 This comes as no surprise, as the shunt routes blood past the liver.

TIPSS has important implications for subsequent orthotopic liver transplantation. For example, TIPSS causes transient (ie, lasts for about 6 months) increases in cardiac volume load. Importantly, pulmonary systolic pressures (as estimated during transthoracic echocardiography) in 1 cohort increased from approximately 30 mm Hg prior to TIPSS to 44 mm Hg in the period immediately after the TIPSS,269 potentially jeopardizing candidacy for transplantation. During transplantation, the shunt must be removed along with the diseased liver. As the shunt by design drains into the hepatic venous circulation, a piggyback technique may be precluded if the shunt protrudes into the proximal hepatic veins. The presence of a TIPSS frequently leads to a complicated and bloody dissection during the hepatectomy phase of liver transplantation. In extreme cases, the shunt can be dislodged and migrate into the right heart or the pulmonary circulation.270

TIPSS is frequently performed "off site" (ie, in a radiology procedure area, rather than an OR), so all of the special concerns for out-of-OR anesthesia apply. Patients presenting for TIPSS are usually severely debilitated and may be acutely ill, and this level of acuity coupled with the out-of-OR location magnifies the effort required to safely care for them.

Monitoring for TIPSS should be tailored to meet the needs of the patient and the anesthetic plan. Standard monitoring is usually sufficient for patients having TIPSS under sedation, monitored anesthesia care, or general anesthesia. TIPSS is usually performed under monitored anesthesia care or general anesthesia. This is because the procedure can require long periods of immobility, and it may be difficult or impossible for an awake patient with massive ascites to remain motionless and supine for the procedure.

The TIPSS procedure typically does not involve large fluid shifts, potential for massive hemorrhage, etc, so a reliable peripheral intravenous catheter is usually sufficient vascular access. The invasive radiologist establishes separate central venous access for the procedure, usually via the right internal jugular vein. The radiologist then tunnels a catheter from the inferior vena cava (actually a hepatic vein) through the liver parenchyma and into the portal circulation. The shunt is then placed via the catheter and dilated within the liver parenchyma.

Complications of TIPSS are relatively common but must be balanced against the complications of no therapy, frequent large-volume paracentesis, or surgical portosystemic shunts, none of which are benign. Complications of TIPSS include those of central venous cannulation in patients with coagulopathy. Complications related to central venous cannulation could be avoided or minimized by using an internal jugular site (which is compressible in the event of inadvertent arterial puncture) and ultrasound guidance to visualize the target vessel during the vascular access procedure. The procedure requires passing guidewires, catheters, and dilators from the superior vena cava, through the right atrium, and into the inferior vena cava. Cardiac perforation and tamponade271 have occurred as rare complications. Acute volume overload269 from the sudden outflow of portal blood into the systemic circulation is a much more frequent complication. Hepatic encephalopathy occurs frequently after TIPSS.272 Encephalopathy is refractory to treatment or prophylaxis,272 and acute onset of encephalopathy may make extubation impossible.

Hepatic Donation

Heart-Beating Cadaveric Donor

Most livers made available for transplantation come from heart-beating cadaveric donors and are obtained in the course of harvesting other organs. Anesthesia care is often complicated by the numerous complex physiologic derangements that are manifested by these organ donors.273 Such physiologic changes are responsible for the loss of up to 25% of potential organ donors.274 Hemodynamic instability commonly develops and may occur in 2 phases. An initial phase may occur soon after brain death, which is characterized by excessive sympathetic activation leading to tachycardia, vasoconstriction, hypertension, and increased cardiac workload. This may be followed by a hypotensive phase in which sympathetic activity is reduced, leading to a loss of vascular tone, decreased cardiac output, and hypotension.275 Hemodynamic stability may be further compromised by volume depletion resulting from the prior use of diuretics to manage elevated ICP, blood loss from injuries, insensible losses, and/or diabetes insipidus associated with damage to the neuro-hypophyseal-hypothalamic axis.

Sympathetic stimulation may be treated with short-acting beta-blockers and vasodilators that may be easily titrated such as nitroprusside and esmolol. As the brain-dead patient progresses into the hypotensive phase, it must be remembered that hypotension can have multiple causes. It is important to identify and appropriately treat the underlying etiology. Hypovolemic patients should receive volume resuscitation to achieve a hematocrit of 30%. Beyond that, crystalloid solutions are appropriate to replace free water as guided by central venous pressure measurements and to maintain or correct electrolyte and glucose concentrations. To reduce volume loss and electrolyte derangements associated with diabetes insipidus, desmopressin acetate (DDAVP) may be administered. Vasopressors and inotropic drugs are appropriate for donors with impaired vascular tone or myocardial function, respectively, to maintain adequate perfusion to organs. In such cases, therapy is most effectively guided by measurements of cardiac function and central filling pressures using a pulmonary artery catheter and/or echocardiography.

Organ donors can also present with significant pulmonary dysfunction.276 Neurogenic pulmonary edema is most commonly observed in patients with increased ICP, and although the etiology is not entirely clear, it is likely related to excessive sympathetic stimulation. Excess pulmonary interstitial and alveolar fluid can be treated with fluid restriction and diuresis, but it should be recognized that a negative fluid balance may compromise the viability of other organs. Other common causes of pulmonary dysfunction in organ donors include pneumonia, pulmonary emboli, mucus plugging, and pulmonary contusions.

An important principle to recognize when caring for organ donors is that the focus of care has shifted from preserving the patient to preserving the function of graft organs. This can best be achieved by being well prepared, as organ harvesting is a major surgical procedure requiring full homeostatic support for the donor organs. In addition to routine intraoperative monitors, intra-arterial and central venous or pulmonary artery catheters are required. Because procurement may be accompanied by significant blood loss, it is important to be adequately prepared with large-gauge intravenous catheters and packed red blood cells for transfusion. Inotropic agents and vasopressors should be readily available to treat hypotension caused by myocardial dysfunction and reduced vascular tone. Nondepolarizing neuromuscular blockers should be used to facilitate surgical exposure and ablate reflex movements mediated by the spinal cord. General anesthesia is not necessary, but general anesthetic drugs may be useful for blunting the hemodynamic response to surgical stimulation associated with the dissection.

As the relative availability of heart-beating cadaveric donor organs has progressively decreased, other organs previously deemed unsuitable or high risk have been evaluated and used for hepatic transplantation. A large retrospective study looking at over 20000 liver transplants in a 4-year period identified 7 characteristics of donor grafts that significantly predicted an increased risk of graft failure and led to the development of the donor risk index (DRI).277 It was initially thought that high-risk organs would confer increased risk in patients with higher MELD scores, relative to patients with lower MELD scores at transplant. This has not proven true, but still leads practitioners to evaluate the decision to proceed with transplantation of a higher DRI organ in a patient or wait until a better organ becomes available, weighing the risk of each.278

Living Donor

The shortage of cadaveric livers has also led to the use of living donors to meet the growing need for liver grafts. Donor safety is a primary concern, as the donor derives no physical benefit from the surgery. Donor deaths have been reported during the perioperative period, and serious complications can occur. Like orthotopic liver transplantation itself, living donor hepatectomy has a steep and long learning curve with many opportunities for morbidity. For example, in 1 program, major complications were frequent in the first 50 living donor patients but declined significantly in the subsequent 50 patients.279 In experienced centers, living donor hepatectomy can be performed with an average blood loss of 1 L and minimal requirements for transfusion.280

Most liver transplantations using living donors involve donor/recipient pairs who are ABO compatible. ABO-incompatible transplantations may be performed in some cases, and recent studies from Japan show that since portal graft infusion therapy has been used in ABO-incompatible living donor liver transplantation, outcomes are similar to those in ABO-compatible transplantations.281 Potential donors should undergo thorough screening to assess their suitability. Such screening includes a detailed history along with a physical and psychologic examination, evaluation of routine laboratory values with particular attention to measurements of liver function, testing for transmissible viral illnesses, and, in some cases, percutaneous liver biopsy. Radiologic imaging studies are also a routine part of the donor evaluation. Doppler ultrasound can be used to detect gross pathologic conditions such as tumors or portal vein thrombosis. Computed tomography and magnetic resonance imaging are useful for defining a potential donor's vascular anatomy and hepatic volume, and to provide a roadmap for surgical planning.282

Typically, a right hepatic lobectomy from an average-sized adult living donor provides sufficient liver mass for an adult recipient. A left hepatic lobectomy from an adult donor provides enough liver mass for a pediatric recipient. This is advantageous for the donor, as the larger right hepatic lobectomy regularly leads to transient measurable compromise in liver synthetic function, with resultant coagulopathy.

General anesthesia for a living donor hepatectomy may be induced and maintained using a variety of techniques. Anesthetic concerns for living donor hepatectomy are similar to those of any major intra-abdominal surgical procedure and include the potential for significant hemorrhage and hemodynamic changes. In particular, systemic vascular resistance commonly decreases after donor hepatic resection, whereas cardiac output and heart rate increases.117 The cause(s) of these changes is not known, but a role for splanchnic mediators, such as endotoxins, has been suggested.283 It has been recommended that maintaining low central filling pressures is useful for reducing intraoperative blood loss and improving surgical exposure.284 However, these benefits must be balanced against the potential increased risk of air embolism.

Because transient coagulopathies are commonly observed in the early postoperative period, the placement of epidural catheters for postoperative analgesia was initially the subject of controversy.285-287 However, pain control requires careful consideration, and some programs use epidural catheters. In 1 study, donor hepatectomy patients had more pain than patients having equivalent-sized right hepatectomy for tumor resection, despite identical pain management regimes, including thoracic epidural use.288 The authors suggested that this finding might be due to longer operative times required for donor hepatectomy.288 Postoperatively, liver donors have significant coagulopathy, which can complicate the timing of discontinuation of epidural analgesia.286,289 On the other hand, thromboelastography studies indicate that liver donors become hypercoagulable during the first postoperative week, despite conventional laboratory studies that indicate elevations of conventional coagulation parameters such as the partial thromboplastin time or the activated prothrombin time and thrombocytopenia.290 This may give a protective effect against epidural hematoma, but this theory has not been tested. In 3 independent studies looking at complications due to epidural placement in donor hepatectomy patients, over 570 patients in 3 centers underwent donor hepatectomies without any episodes of epidural hematomas despite postoperative coagulation changes.137,291,292

Donation after Cardiac Death

The number of livers from brain-dead donors has been relatively stagnant, and living donation is not a common option. The shortage of organs has resulted in renewed interest in a procedure for recovering organs known as donation after cardiac death. This term refers to a donation protocol for patients who have sustained a traumatic brain injury but do not meet the definition of brain death and thus cannot be declared brain dead. Nevertheless, families may realize that there is no hope for recovery and decide to withdraw invasive life support. Once such a decision has been made, the family may decide to donate the patient's organs after cardiac death has occurred.

Donations after cardiac death occur only after patients are declared dead after cardiac and respiratory arrest following the removal of life support. Donation after cardiac death is only considered after the family has decided to withdraw life support. The patient is taken to the operating room, usually with the family in attendance. There, the patient is extubated, vasoactive infusions may be discontinued, and the patient is allowed to die peacefully. The family leaves the room, and a surgical removal of organs for transplantation ensues.

Donation after cardiac death exposes the donor liver to a period of warm ischemia that does not occur in beating-heart donors. Liver viability declines as a function of the elapsed time after cardiac arrest in animals.293 In humans, the immediate outcomes appear to be worse in recipients of donation-after-cardiac-death livers, relative to recipients of beating-heart donor organs, but the overall outcomes appear promising relative to no organ at all.294

Despite the fact that donation after cardiac death involves patients who are dead by every definition, and thus have no use for homeostatic support, there is much that the anesthesia team can contribute to these cases. Planned death in the operating room, with grieving family present in large numbers and in civilian dress, is an extraordinary event and flies in the face of many of the assumptions and mores of operating room personnel. Anesthesiologists can manage operating room access to allow donation to occur promptly and with respect to the deceased and his or her family, even to the point of mediating the cancellation of elective surgery to facilitate these singularly lifesaving events.

The anesthesia teams should sequence the preparation of recipient(s) to minimize donor organ ischemic time if possible. Anesthesiologists do not currently have any direct interaction with the donor, except possibly to perform the extubation. Extubation should be skillfully handled, both to protect the family members from unnecessary psychologic trauma and to minimize the risk of aspiration that spoils the lungs for donation. Anesthesiologists may become more involved in donation after cardiac death cases, as they may be asked to reintubate the trachea for lung protection (allowing lung donation) after asystole occurs. In many centers, however, no member of the anesthesia team may be present until after the death of the donor occurs.

• Abdalla EK, Noun R, Belghiti J. Hepatic vascular occlusion: which technique? Surg Clin North Am. 2004;84(2):563-585.
• Emond JC, Samstein B, Renz JF. A critical evaluation of hepatic resection in cirrhosis: optimizing patient selection and outcomes. World J Surg. 2005;29(2):124-130.
• Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopulmonary syndrome. Lancet. 2004;363(9419):1461-1468.
• Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg. 2002;236(4):397-406; discussion 406-397.
• Keeffe BG, Valantine H, Keeffe EB. Detection and treatment of coronary artery disease in liver transplant candidates. Liver Transpl. 2001;7(9):755-761.
• Pham PT, Pham PC, Rastogi A, Wilkinson AH. Review article: current management of renal dysfunction in the cirrhotic patient. Aliment Pharmacol Ther. 2005;21(8):949-961.
• Reddy K, Mallett S, Peachey T. Venovenous bypass in orthotopic liver transplantation: time for a rethink? Liver Transpl. 2005;11(7):741-749.
• Xia VW, Steadman RH. Antifibrinolytics in orthotopic liver transplantation: current status and controversies. Liver Transpl. 2005;11(1):10-18.